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Zhu Y, Zhang L, Wang Z, Li T, Chen Y, Lu L, Liu H, Kong D, Peng Y, Chen X, Hu C, Chen H, Guo A. Circular RNA ZNF277 Sponges miR-378d to Inhibit the Intracellular Survival of Mycobacterium tuberculosis by Upregulating Rab10. Cells 2025; 14:262. [PMID: 39996735 PMCID: PMC11853707 DOI: 10.3390/cells14040262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 01/29/2025] [Accepted: 02/10/2025] [Indexed: 02/26/2025] Open
Abstract
Circular RNAs (circRNAs) are covalently closed non-coding RNAs formed by back-splicing, lacking a 5' cap and poly-A tail. They could act as important regulatory factors in the host's anti-tuberculosis immune process, but only a few have been identified, and their molecular mechanisms remain largely unclear. Here, we identified a novel circRNA, circ-ZNF277, which responds to Mycobacterium tuberculosis (Mtb) infection in THP-1 cells. Circ-ZNF277 binds microRNA-378d (miR-378d) in vivo. The expression level of circ-ZNF277 affects the clearance of the intracellular Mtb in THP-1 cells. Mechanistically, more circ-ZNF277 molecules could absorb more miR-378d, thereby competitively activating the NF-κB signaling pathway, promoting the release of pro-inflammatory cytokines including interleukins IL-1β and IL-6, and tumor necrosis factor-α (TNF-α), and inhibiting the survival of intracellular Mtb. Expressing miR-378d or si-Rab10 targeting the transcription of Rab10 could antagonize the effects of overexpression of circ-ZNF277, resulting in the reduced intracellular survival of Mtb. In summary, circ-ZNF277 inhibits the intracellular survival of Mtb via the miR-378d/Rab10 axis. This finding represents a novel mechanism of circular RNA in regulating host immune responses during Mtb infection.
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Affiliation(s)
- Yifan Zhu
- National Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (Y.Z.); (L.Z.); (X.C.)
- National Professional Laboratory for Animal Tuberculosis (Wuhan), Ministry of Agriculture and Rural Affairs, International Research Center for Animal Disease, Ministry of Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Lei Zhang
- National Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (Y.Z.); (L.Z.); (X.C.)
- National Professional Laboratory for Animal Tuberculosis (Wuhan), Ministry of Agriculture and Rural Affairs, International Research Center for Animal Disease, Ministry of Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Zijian Wang
- National Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (Y.Z.); (L.Z.); (X.C.)
- National Professional Laboratory for Animal Tuberculosis (Wuhan), Ministry of Agriculture and Rural Affairs, International Research Center for Animal Disease, Ministry of Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Ting Li
- National Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (Y.Z.); (L.Z.); (X.C.)
- National Professional Laboratory for Animal Tuberculosis (Wuhan), Ministry of Agriculture and Rural Affairs, International Research Center for Animal Disease, Ministry of Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Yingyu Chen
- National Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (Y.Z.); (L.Z.); (X.C.)
- National Professional Laboratory for Animal Tuberculosis (Wuhan), Ministry of Agriculture and Rural Affairs, International Research Center for Animal Disease, Ministry of Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Lu Lu
- National Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (Y.Z.); (L.Z.); (X.C.)
- National Professional Laboratory for Animal Tuberculosis (Wuhan), Ministry of Agriculture and Rural Affairs, International Research Center for Animal Disease, Ministry of Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Han Liu
- National Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (Y.Z.); (L.Z.); (X.C.)
- National Professional Laboratory for Animal Tuberculosis (Wuhan), Ministry of Agriculture and Rural Affairs, International Research Center for Animal Disease, Ministry of Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Delai Kong
- National Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (Y.Z.); (L.Z.); (X.C.)
- National Professional Laboratory for Animal Tuberculosis (Wuhan), Ministry of Agriculture and Rural Affairs, International Research Center for Animal Disease, Ministry of Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Yongchong Peng
- National Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (Y.Z.); (L.Z.); (X.C.)
- National Professional Laboratory for Animal Tuberculosis (Wuhan), Ministry of Agriculture and Rural Affairs, International Research Center for Animal Disease, Ministry of Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Xi Chen
- National Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (Y.Z.); (L.Z.); (X.C.)
- National Professional Laboratory for Animal Tuberculosis (Wuhan), Ministry of Agriculture and Rural Affairs, International Research Center for Animal Disease, Ministry of Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Changmin Hu
- National Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (Y.Z.); (L.Z.); (X.C.)
- National Professional Laboratory for Animal Tuberculosis (Wuhan), Ministry of Agriculture and Rural Affairs, International Research Center for Animal Disease, Ministry of Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Huanchun Chen
- National Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (Y.Z.); (L.Z.); (X.C.)
- National Professional Laboratory for Animal Tuberculosis (Wuhan), Ministry of Agriculture and Rural Affairs, International Research Center for Animal Disease, Ministry of Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Aizhen Guo
- National Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (Y.Z.); (L.Z.); (X.C.)
- National Professional Laboratory for Animal Tuberculosis (Wuhan), Ministry of Agriculture and Rural Affairs, International Research Center for Animal Disease, Ministry of Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
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Gunasekaran H, Ranganathan UD, Bethunaickan R. The importance of inflammatory biomarkers in detecting and managing latent tuberculosis infection. Front Immunol 2025; 16:1538127. [PMID: 39981231 PMCID: PMC11839662 DOI: 10.3389/fimmu.2025.1538127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 01/17/2025] [Indexed: 02/22/2025] Open
Abstract
Infection with Mycobacterium tuberculosis (Mtb) triggers an autoimmune-like response in the host leading to further complications. One of the major concerns in eliminating Tuberculosis (TB) is identifying individuals with Latent Tuberculosis Infection (LTBI) who serve as major reservoirs of Mtb making them the important target group for TB eradication. Since no gold standard tests are available for detecting LTBI, the global burden of LTBI cannot be precisely determined. Since LTBI poses several challenges to worldwide healthcare, managing LTBI must be the key priority to achieve a TB-free status. The inflammatory mediators play a major role in determining the outcome of the Mtb infection and also their levels seem to change according to the disease severity. Identification of inflammatory mediators and utilizing them as diagnostic biomarkers for detecting the various stages of TB disease might help identify the reservoirs of Mtb infection even before they become symptomatic so that preventative treatment can be started early. In summary, this review primarily focuses on exploring different inflammatory markers along the course of the Mtb infection. Identifying LTBI-specific biomarkers helps to identify individuals who are at higher risk of developing TB and preparing them to adhere to preventive therapy thus minimizing the global burden of TB.
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Affiliation(s)
- Harinisri Gunasekaran
- Department of Immunology, ICMR-National Institute for Research in Tuberculosis, Chennai, India
- University of Madras, Chennai, India
| | - Uma Devi Ranganathan
- Department of Immunology, ICMR-National Institute for Research in Tuberculosis, Chennai, India
- University of Madras, Chennai, India
- Faculty of Medical Research, Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Ramalingam Bethunaickan
- Department of Immunology, ICMR-National Institute for Research in Tuberculosis, Chennai, India
- University of Madras, Chennai, India
- Faculty of Medical Research, Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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Abdelaal HFM, Berube BJ, Podell BK, Harband MH, Gary HE, Perez-Jaimes M, Ackart DF, Reese VA, Larsen SE, Pecor T, Wilkins DZ, Parish T, Maloney-Norcross SE, Mecham JB, Hickey AJ, Baldwin SL, Coler RN. Assessment of tuberculosis drug efficacy using preclinical animal models and in vitro predictive techniques. NPJ ANTIMICROBIALS AND RESISTANCE 2024; 2:49. [PMID: 39843983 PMCID: PMC11721416 DOI: 10.1038/s44259-024-00066-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 11/20/2024] [Indexed: 01/24/2025]
Abstract
Tuberculosis (TB) killed approximately 1.3 million people in 2022 and remains a leading cause of death from the bacteria Mycobacterium tuberculosis (M.tb); this number of deaths was surpassed only by COVID-19, caused by the SARS-CoV-2 virus. The alarming emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) M.tb strains presents an urgent need for effective new treatments. Our study aimed to determine the synergistic effects of antibiotic combinations against M.tb. Using a high-throughput in vitro checkerboard assay, we evaluated the interactions of Bedaquiline (BDQ) and other antibiotics including Capreomycin (CAP), Linezolid (LIN), and Sutezolid (SUT) against M.tb H37Rv. BDQ and CAP demonstrated in vitro enhanced effect, which prompted further investigation in vivo using the murine low dose aerosol (LDA) model. After aerosol challenge with M.tb, C57BL/6 mice were treated with BDQ, CAP, or their combination, starting 28 days post-infection. The antimicrobial treatment lasted four weeks, and the bacterial burden in lung and spleen tissues was assessed at the end of treatment. At 4 weeks post-treatment, a significant reduction in bacterial load was observed within the lungs and spleens of mice given BDQ alone or given as a BDQ/CAP combination compared to the untreated group. In contrast, CAP monotherapy led to an increase in bacterial load within the lung and no significant difference in bacterial burden in the spleen in comparison to the untreated mice. These results were confirmed in the guinea pig model of TB, where both BDQ and the BDQ/CAP combination treatment led to a decrease in bacterial burden in the lung and spleen, whereas CAP had no significant effect on bacterial burden at the 4-week post treatment timepoint. We next determined whether there may be differences in vitro with the BDQ/CAP combination against M.tb lineages 1, 2 and 4. We determined that in vitro enhanced effect was not observed in some representative strains of M.tb lineage 4, indicating variability in drug effectiveness across M.tb lineages. This research underscores the complexity of TB treatment and the critical need for innovative approaches to combat this global health threat.
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Affiliation(s)
- Hazem F M Abdelaal
- Seattle Children's Research Institute, Center for Global Infectious Disease Research, Seattle, WA, 98145, USA
| | - Bryan J Berube
- Seattle Children's Research Institute, Center for Global Infectious Disease Research, Seattle, WA, 98145, USA
- HDT BioCorp, Seattle, WA, 98102, USA
| | - Brendan K Podell
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, 80523, USA
| | - Matthew H Harband
- Seattle Children's Research Institute, Center for Global Infectious Disease Research, Seattle, WA, 98145, USA
| | - Hadley E Gary
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, 80523, USA
| | - Martin Perez-Jaimes
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, 80523, USA
| | - David F Ackart
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, 80523, USA
| | - Valerie A Reese
- Seattle Children's Research Institute, Center for Global Infectious Disease Research, Seattle, WA, 98145, USA
| | - Sasha E Larsen
- Seattle Children's Research Institute, Center for Global Infectious Disease Research, Seattle, WA, 98145, USA
| | - Tiffany Pecor
- Seattle Children's Research Institute, Center for Global Infectious Disease Research, Seattle, WA, 98145, USA
| | - David Z Wilkins
- Seattle Children's Research Institute, Center for Global Infectious Disease Research, Seattle, WA, 98145, USA
| | - Tanya Parish
- Seattle Children's Research Institute, Center for Global Infectious Disease Research, Seattle, WA, 98145, USA
| | - Sara E Maloney-Norcross
- Technology Advancement and Commercialization, RTI International, Research Triangle Park, Triangle Park, NC, 27709, USA
| | - Jeffrey B Mecham
- Technology Advancement and Commercialization, RTI International, Research Triangle Park, Triangle Park, NC, 27709, USA
| | - Anthony J Hickey
- Technology Advancement and Commercialization, RTI International, Research Triangle Park, Triangle Park, NC, 27709, USA
| | - Susan L Baldwin
- Seattle Children's Research Institute, Center for Global Infectious Disease Research, Seattle, WA, 98145, USA
| | - Rhea N Coler
- Seattle Children's Research Institute, Center for Global Infectious Disease Research, Seattle, WA, 98145, USA.
- Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, 98195, USA.
- Department of Global Health, University of Washington, Seattle, WA, 98195, USA.
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Li W, Luo X, Zheng XQ, Li QL, Li Z, Meng QQ, Zeng YL, Lin Y, Yang TC. Treponema pallidum protein Tp0136 promotes angiogenesis to facilitate the dissemination of Treponema pallidum. Emerg Microbes Infect 2024; 13:2382236. [PMID: 39017656 PMCID: PMC11299452 DOI: 10.1080/22221751.2024.2382236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/09/2024] [Accepted: 07/16/2024] [Indexed: 07/18/2024]
Abstract
The incompletely eliminated Treponema pallidum (T. pallidum) during primary syphilis chancre infection can result in the progression of secondary, tertiary, or latent syphilis in individuals, suggesting that T. pallidum has successfully evaded the immune response and spread to distant sites. The mechanism underlying the dissemination of T. pallidum is unclear. Here, a syphilitic rabbit model dorsal-injected with recombinant Tp0136 protein or Tp0136 antibody subcutaneously was used to demonstrate the role of Tp0136 protein in promoting the dissemination of T. pallidum to the testis and angiogenesis in vivo; vascular endothelial cell line HMEC-1 was employed to display that Tp0136 protein enhances the angiogenesis. Furthermore, the three-dimensional microfluidic angiogenesis system showed that the angiogenesis would heighten vascular permeability. Then transcriptome sequencing analysis, in conjunction with cell-level validation, elucidated the critical role of the PI3K-AKT signaling pathway in the promotion of angiogenesis by Tp0136 protein, resulting in heightened permeability. These findings elucidate the strategy employed by T. pallidum in evading immune clearance.
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Affiliation(s)
- Wei Li
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | - Xi Luo
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | - Xin-Qi Zheng
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | - Qiu-Ling Li
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | - Ze Li
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | - Qing-Qi Meng
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | - Yan-Li Zeng
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
- Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
| | - Yu Lin
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
- Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
- Xiamen Clinical Laboratory Quality Control Center, Xiamen, People’s Republic of China
| | - Tian-Ci Yang
- Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
- Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, People’s Republic of China
- Xiamen Clinical Laboratory Quality Control Center, Xiamen, People’s Republic of China
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Al-Bari MAA, Peake N, Eid N. Tuberculosis-diabetes comorbidities: Mechanistic insights for clinical considerations and treatment challenges. World J Diabetes 2024; 15:853-866. [PMID: 38766427 PMCID: PMC11099355 DOI: 10.4239/wjd.v15.i5.853] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 02/08/2024] [Accepted: 03/21/2024] [Indexed: 05/10/2024] Open
Abstract
Tuberculosis (TB) remains a leading cause of death among infectious diseases, particularly in poor countries. Viral infections, multidrug-resistant and ex-tensively drug-resistant TB strains, as well as the coexistence of chronic illnesses such as diabetes mellitus (DM) greatly aggravate TB morbidity and mortality. DM [particularly type 2 DM (T2DM)] and TB have converged making their control even more challenging. Two contemporary global epidemics, TB-DM behaves like a syndemic, a synergistic confluence of two highly prevalent diseases. T2DM is a risk factor for developing more severe forms of multi-drug resistant-TB and TB recurrence after preventive treatment. Since a bidirectional relationship exists between TB and DM, it is necessary to concurrently treat both, and promote recommendations for the joint management of both diseases. There are also some drug-drug interactions resulting in adverse treatment outcomes in TB-DM patients including treatment failure, and reinfection. In addition, autophagy may play a role in these comorbidities. Therefore, the TB-DM comorbidities present several health challenges, requiring a focus on multidisciplinary collaboration and integrated strategies, to effectively deal with this double burden. To effectively manage the comorbidity, further screening in affected countries, more suitable drugs, and better treatment strategies are required.
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Affiliation(s)
| | - Nicholas Peake
- Biosciences and Chemistry and Biomolecular Research Centre, Sheffield Hallam University, Sheffield S1 1WB, United Kingdom
| | - Nabil Eid
- Department of Anatomy, Division of Human Biology, School of Medicine, International Medical University, Kuala Lumpur 57000, Malaysia
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Tatano Y, Shimizu T, Sano C, Tomioka H. Roles of autophagy in killing of mycobacterial pathogens by host macrophages - Effects of some medicinal plants. Eur J Microbiol Immunol (Bp) 2024; 14:26-36. [PMID: 38349363 PMCID: PMC10895364 DOI: 10.1556/1886.2023.00062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 01/29/2024] [Indexed: 02/24/2024] Open
Abstract
Autophagy is a cellular stress-induced intracellular process, through which damaged cellular components are decomposed via lysosomal degradation. This process plays important roles in host innate immunity, particularly the elimination of intracellular pathogens inside host macrophages. A more detailed understanding of the roles of autophagic events in the effective manifestation of macrophagic antimycobacterial activity is needed. Furthermore, the effects of medicinal plants on macrophagic autophagy response to mycobacterial infection need to be clarified. We herein examined the significance of autophagic events in the manifestation of host immunity during mycobacterial infection, by performing a literature search using PubMed. Recent studies demonstrated that autophagy up-regulated macrophage functions related to the intracellular killing of mycobacteria, even when pathogens were residing within the cytoplasm of macrophages. The majority of medicinal plants potentiated macrophagic autophagy, thereby enhancing their antimycobacterial functions. In contrast, most medicinal plants down-regulate the development and activation of the Th17 cell population, which reduces macrophage antimycobacterial activity. These opposing effects of medicinal plants on macrophage autophagy (enhancement) and Th17 cell functions (inhibition) may provide a plausible explanation for the clinical observation of their modest efficacy in the treatment of mycobacterial infections.
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Affiliation(s)
- Yutaka Tatano
- 1Department of Pharmaceutical Sciences, International University of Health and Welfare, Fukuoka, Japan
| | - Toshiaki Shimizu
- 2Department of Nutrition Administration, Yasuda Women's University, Hiroshima, Japan
| | - Chiaki Sano
- 3Department of Community Medicine Management, Faculty of Medicine, Shimane University, Izumo Japan
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Yuk JM, Kim JK, Kim IS, Jo EK. TNF in Human Tuberculosis: A Double-Edged Sword. Immune Netw 2024; 24:e4. [PMID: 38455468 PMCID: PMC10917576 DOI: 10.4110/in.2024.24.e4] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 01/01/2024] [Accepted: 01/10/2024] [Indexed: 03/09/2024] Open
Abstract
TNF, a pleiotropic proinflammatory cytokine, is important for protective immunity and immunopathology during Mycobacterium tuberculosis (Mtb) infection, which causes tuberculosis (TB) in humans. TNF is produced primarily by phagocytes in the lungs during the early stages of Mtb infection and performs diverse physiological and pathological functions by binding to its receptors in a context-dependent manner. TNF is essential for granuloma formation, chronic infection prevention, and macrophage recruitment to and activation at the site of infection. In animal models, TNF, in cooperation with chemokines, contributes to the initiation, maintenance, and clearance of mycobacteria in granulomas. Although anti-TNF therapy is effective against immune diseases such as rheumatoid arthritis, it carries the risk of reactivating TB. Furthermore, TNF-associated inflammation contributes to cachexia in patients with TB. This review focuses on the multifaceted role of TNF in the pathogenesis and prevention of TB and underscores the importance of investigating the functions of TNF and its receptors in the establishment of protective immunity against and in the pathology of TB. Such investigations will facilitate the development of therapeutic strategies that target TNF signaling, which makes beneficial and detrimental contributions to the pathogenesis of TB.
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Affiliation(s)
- Jae-Min Yuk
- Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon 35015, Korea
- Department of Medical Science, Chungnam National University College of Medicine, Daejeon 35015, Korea
- Department of Infection Biology, Chungnam National University College of Medicine, Daejeon 35015, Korea
| | - Jin Kyung Kim
- Department of Microbiology, Keimyung University School of Medicine, Daegu 42601, Korea
| | - In Soo Kim
- Department of Medical Science, Chungnam National University College of Medicine, Daejeon 35015, Korea
- Department of Pharmacology, Chungnam National University College of Medicine, Daejeon 35015, Korea
| | - Eun-Kyeong Jo
- Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon 35015, Korea
- Department of Medical Science, Chungnam National University College of Medicine, Daejeon 35015, Korea
- Department of Microbiology, Chungnam National University College of Medicine, Daejeon 35015, Korea
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Nguyen M, Ahn P, Dawi J, Gargaloyan A, Kiriaki A, Shou T, Wu K, Yazdan K, Venketaraman V. The Interplay between Mycobacterium tuberculosis and Human Microbiome. Clin Pract 2024; 14:198-213. [PMID: 38391403 PMCID: PMC10887847 DOI: 10.3390/clinpract14010017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/16/2024] [Accepted: 01/17/2024] [Indexed: 02/24/2024] Open
Abstract
Tuberculosis (TB), a respiratory disease caused by Mycobacterium tuberculosis (Mtb), is a significant cause of mortality worldwide. The lung, a breeding ground for Mtb, was once thought to be a sterile environment, but has now been found to host its own profile of microbes. These microbes are critical in the development of the host immune system and can produce metabolites that aid in host defense against various pathogens. Mtb infection as well as antibiotics can shift the microbial profile, causing dysbiosis and dampening the host immune response. Additionally, increasing cases of drug resistant TB have impacted the success rates of the traditional therapies of isoniazid, rifampin, pyrazinamide, and ethambutol. Recent years have produced tremendous research into the human microbiome and its role in contributing to or attenuating disease processes. Potential treatments aimed at altering the gut-lung bacterial axis may offer promising results against drug resistant TB and help mitigate the effects of TB.
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Affiliation(s)
- Michelle Nguyen
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Phillip Ahn
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - John Dawi
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Areg Gargaloyan
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Anthony Kiriaki
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Tiffany Shou
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Kevin Wu
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Kian Yazdan
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Vishwanath Venketaraman
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
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Xie J, Meijer AH. Xenophagy receptors Optn and p62 and autophagy modulator Dram1 independently promote the zebrafish host defense against Mycobacterium marinum. Front Cell Infect Microbiol 2024; 13:1331818. [PMID: 38264729 PMCID: PMC10803470 DOI: 10.3389/fcimb.2023.1331818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 12/18/2023] [Indexed: 01/25/2024] Open
Abstract
Anti-bacterial autophagy, also known as xenophagy, is a crucial innate immune process that helps maintain cellular homeostasis by targeting invading microbes. This defense pathway is widely studied in the context of infections with mycobacteria, the causative agents of human tuberculosis and tuberculosis-like disease in animal models. Our previous work in a zebrafish tuberculosis model showed that host defense against Mycobacterium marinum (Mm) is impaired by deficiencies in xenophagy receptors, optineurin (Optn) or sequestome 1 (p62), and Damage-regulated autophagy modulator 1 (Dram1). However, the interdependency of these receptors and their interaction with Dram1 remained unknown. In the present study, we used single and double knockout zebrafish lines in combination with overexpression experiments. We show that Optn and p62 can compensate for the loss of each other's function, as their overexpression restores the infection susceptibility of the mutant phenotypes. Similarly, Dram1 can compensate for deficiencies in Optn and p62, and, vice versa, Optn and p62 compensate for the loss of Dram1, indicating that these xenophagy receptors and Dram1 do not rely on each other for host defense against Mm. In agreement, Dram1 overexpression in optn/p62 double mutants restored the interaction of autophagosome marker Lc3 with Mm. Finally, optn/p62 double mutants displayed more severe infection susceptibility than the single mutants. Taken together, these results suggest that Optn and p62 do not function downstream of each other in the anti-mycobacterial xenophagy pathway, and that the Dram1-mediated defense against Mm infection does not rely on specific xenophagy receptors.
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Ocampo JC, Alzate JF, Barrera LF, Baena A. Tuberculosis Severity Predictive Model Using Mtb Variants and Serum Biomarkers in a Colombian Cohort of APTB Patients. Biomedicines 2023; 11:3110. [PMID: 38137331 PMCID: PMC10740695 DOI: 10.3390/biomedicines11123110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/27/2023] [Accepted: 11/04/2023] [Indexed: 12/24/2023] Open
Abstract
Currently, tuberculosis (TB) is a bacterial infection caused by Mycobacterium tuberculosis (Mtb) that primarily affects the lungs. The severity of active pulmonary TB (APTB) is an important determinant of transmission, morbidity, mortality, disease experience, and treatment outcomes. Several publications have shown a high prevalence of disabling complications in individuals who have had severe APTB. Furthermore, certain strains of Mtb were associated with more severe disease outcomes. The use of biomarkers to predict severe APTB patients who are candidates for host-directed therapies, due to the high risk of developing post-tuberculous lung disease (PTLD), has not yet been implemented in the management of TB patients. We followed 108 individuals with APTB for 6 months using clinical tools, flow cytometry, and whole-genome sequencing (WGS). The median age of the study population was 26.5 years, and the frequency of women was 53.7%. In this study, we aimed to identify biomarkers that could help us to recognize individuals with APTB and improve our understanding of the immunopathology in these individuals. In this study, we conducted a follow-up on the treatment progress of 121 cases of APTB. The follow-up process commenced at the time of diagnosis (T0), continued with a control visit at 2 months (T2), and culminated in an exit appointment at 6 months following the completion of medical treatment (T6). People classified with severe APTB showed significantly higher levels of IL-6 (14.7 pg/mL; p < 0.05) compared to those with mild APTB (7.7 pg/mL) at T0. The AUCs for the ROC curves and the Matthews correlation coefficient values (MCC) demonstrate correlations ranging from moderate to very strong. We conducted WGS on 88 clinical isolates of Mtb, and our analysis revealed a total of 325 genes with insertions and deletions (Indels) within their coding regions when compared to the Mtb H37Rv reference genome. The pattern of association was found between serum levels of CHIT1 and the presence of Indels in Mtb isolates from patients with severe APTB. A key finding in our study was the high levels of CHIT1 in severe APTB patients. We identified a biomarker profile (IL-6, IFN-γ, IL-33, and CHIT1) that allows us to identify individuals with severe APTB, as well as the identification of a panel of polymorphisms (125) in clinical isolates of Mtb from individuals with severe APTB. Integrating these findings into a predictive model of severity would show promise for the management of APTB patients in the future, to guide host-directed therapy and reduce the prevalence of PTLD.
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Affiliation(s)
- Juan C. Ocampo
- Grupo de Inmunología Celular e Inmunogenética (GICIG), Universidad de Antioquia (UdeA), Medellín 050010, Colombia; (J.C.O.); (L.F.B.)
| | - Juan F. Alzate
- Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad de Antioquia (UdeA), Medellín 050010, Colombia;
- Centro Nacional de Secuenciación Genómica (CNSG), Facultad de Medicina, Universidad de Antioquia (UdeA), Medellín 050010, Colombia
| | - Luis F. Barrera
- Grupo de Inmunología Celular e Inmunogenética (GICIG), Universidad de Antioquia (UdeA), Medellín 050010, Colombia; (J.C.O.); (L.F.B.)
- Instituto de Investigaciones Médicas, Universidad de Antioquia (UdeA), Medellín 050010, Colombia
| | - Andres Baena
- Grupo de Inmunología Celular e Inmunogenética (GICIG), Universidad de Antioquia (UdeA), Medellín 050010, Colombia; (J.C.O.); (L.F.B.)
- Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad de Antioquia (UdeA), Medellín 050010, Colombia;
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11
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Wang N, Yao Y, Qian Y, Qiu D, Cao H, Xiang H, Wang J. Cargoes of exosomes function as potential biomarkers for Mycobacterium tuberculosis infection. Front Immunol 2023; 14:1254347. [PMID: 37928531 PMCID: PMC10622749 DOI: 10.3389/fimmu.2023.1254347] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 10/02/2023] [Indexed: 11/07/2023] Open
Abstract
Exosomes as double-membrane vesicles contain various contents of lipids, proteins, mRNAs and non-coding RNAs, and involve in multiple physiological processes, for instance intercellular communication and immunomodulation. Currently, numerous studies found that the components of exosomal proteins, nucleic acids or lipids released from host cells are altered following infection with Mycobacterium tuberculosis. Exosomal contents provide excellent biomarkers for the auxiliary diagnosis, efficacy evaluation, and prognosis of tuberculosis. This study aimed to review the current literatures detailing the functions of exosomes in the procedure of M. tuberculosis infection, and determine the potential values of exosomes as biomarkers to assist in the diagnosis and monitoring of tuberculosis.
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Affiliation(s)
- Nan Wang
- Department of Clinical Laboratory, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, Jiangsu, China
| | - Yongliang Yao
- Department of Clinical Laboratory, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, Jiangsu, China
| | - Yingfen Qian
- Department of Clinical Laboratory, Kunshan Fourth People’s Hospital, Suzhou, Jiangsu, China
| | - Dewen Qiu
- Department of Clinical Laboratory, Jiangxi Maternal and Child Health Hospital Maternal and Child Heath Hospital of Nanchang College, Nanchang, China
| | - Hui Cao
- Department of Food and Nutrition Safety, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
| | - Huayuan Xiang
- Department of Clinical Laboratory, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, Jiangsu, China
| | - Jianjun Wang
- Department of Clinical Laboratory, Kunshan Hospital Affiliated to Jiangsu University, Suzhou, Jiangsu, China
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12
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Wei J, Guo F, Song Y, Xu K, Lin F, Li K, Li B, Qian Z, Wang X, Wang H, Xu T. Transcriptional analysis of human peripheral blood mononuclear cells stimulated by Mycobacterium tuberculosis antigen. Front Cell Infect Microbiol 2023; 13:1255905. [PMID: 37818041 PMCID: PMC10561294 DOI: 10.3389/fcimb.2023.1255905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 09/04/2023] [Indexed: 10/12/2023] Open
Abstract
Background Mycobacterium tuberculosis antigen (Mtb-Ag) is a polypeptide component with a molecular weight of 10-14 kDa that is obtained from the supernatant of the H37Ra strain after heat treatment. It stimulates the activation and proliferation of γδT cells in the blood to produce an immune response against tuberculosis. Mtb-Ag is therefore crucial for classifying and detecting the central genes and key pathways involved in TB initiation and progression. Methods In this study, we performed high-throughput RNA sequencing of peripheral blood mononuclear cells (PBMC) from Mtb-Ag-stimulated and control samples to identify differentially expressed genes and used them for gene ontology (GO) and a Kyoto Encyclopedia of Genomes (KEGG) enrichment analysis. Meanwhile, we used PPI protein interaction network and Cytoscape analysis to identify key genes and qRT-PCR to verify differential gene expression. Single-gene enrichment analysis (GSEA) was used further to elucidate the potential biological functions of key genes. Analysis of immune cell infiltration and correlation of key genes with immune cells after Mtb-Ag-stimulated using R language. Results We identified 597 differentially expressed genes in Mtb-Ag stimulated PBMCs. KEGG and GSEA enrichment analyzed the cellular pathways related to immune function, and DEGs were found to be primarily involved in the TNF signaling pathway, the IL-17 signaling pathway, the JAK-STAT signaling pathway, cytokine-cytokine receptor interactions, and the NF-κB signaling pathway. Wayne analysis using GSEA, KEGG, and the protein-protein interaction (PPI) network showed that 34 genes, including PTGS2, IL-1β, IL-6, TNF and IFN-γ et al., were co-expressed in the five pathways and all were up-regulated by Mtb-Ag stimulation. Twenty-four DEGs were identified using qRT-PCR, including fourteen up-regulated genes (SERPINB7, IL20, IFNG, CSF2, PTGS2, TNF-α, IL36G, IL6, IL10, IL1A, CXCL1, CXCL8, IL4, and CXCL3) and ten down-regulated genes (RTN1, CSF1R CD14, C5AR1, CXCL16, PLXNB2, OLIG1, EEPD1, ENG, and CCR1). These findings were consistent with the RNA-Seq results. Conclusion The transcriptomic features associated with Mtb-Ag provide the scientific basis for exploring the intracellular immune mechanisms against Mtb. However, more studies on these DEGs in pathways associated with Mtb-Ag stimulation are needed to elucidate the underlying pathologic mechanisms of Mtb-Ag during Mtb infection.
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Affiliation(s)
- Jing Wei
- Laboratory Medicine Experimental Center, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Fangzheng Guo
- Laboratory Medicine Experimental Center, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Yamin Song
- Laboratory Medicine Experimental Center, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Kun Xu
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Feiyang Lin
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Kangsheng Li
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Baiqing Li
- Laboratory Medicine Experimental Center, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
- Department of Immunology, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
| | - Zhongqing Qian
- Laboratory Medicine Experimental Center, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
- Department of Immunology, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
| | - Xiaojing Wang
- Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, Bengbu Medical College, Bengbu, China
| | - Hongtao Wang
- Laboratory Medicine Experimental Center, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
- Department of Immunology, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
| | - Tao Xu
- Laboratory Medicine Experimental Center, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
- Department of Clinical Laboratory and Diagnostics, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
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13
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Klever AM, Alexander KA, Almeida D, Anderson MZ, Ball RL, Beamer G, Boggiatto P, Buikstra JE, Chandler B, Claeys TA, Concha AE, Converse PJ, Derbyshire KM, Dobos KM, Dupnik KM, Endsley JJ, Endsley MA, Fennelly K, Franco-Paredes C, Hagge DA, Hall-Stoodley L, Hayes D, Hirschfeld K, Hofman CA, Honda JR, Hull NM, Kramnik I, Lacourciere K, Lahiri R, Lamont EA, Larsen MH, Lemaire T, Lesellier S, Lee NR, Lowry CA, Mahfooz NS, McMichael TM, Merling MR, Miller MA, Nagajyothi JF, Nelson E, Nuermberger EL, Pena MT, Perea C, Podell BK, Pyle CJ, Quinn FD, Rajaram MVS, Mejia OR, Rothoff M, Sago SA, Salvador LCM, Simonson AW, Spencer JS, Sreevatsan S, Subbian S, Sunstrum J, Tobin DM, Vijayan KKV, Wright CTO, Robinson RT. The Many Hosts of Mycobacteria 9 (MHM9): A conference report. Tuberculosis (Edinb) 2023; 142:102377. [PMID: 37531864 PMCID: PMC10529179 DOI: 10.1016/j.tube.2023.102377] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/10/2023] [Accepted: 07/17/2023] [Indexed: 08/04/2023]
Abstract
The Many Hosts of Mycobacteria (MHM) meeting series brings together basic scientists, clinicians and veterinarians to promote robust discussion and dissemination of recent advances in our knowledge of numerous mycobacterial diseases, including human and bovine tuberculosis (TB), nontuberculous mycobacteria (NTM) infection, Hansen's disease (leprosy), Buruli ulcer and Johne's disease. The 9th MHM conference (MHM9) was held in July 2022 at The Ohio State University (OSU) and centered around the theme of "Confounders of Mycobacterial Disease." Confounders can and often do drive the transmission of mycobacterial diseases, as well as impact surveillance and treatment outcomes. Various confounders were presented and discussed at MHM9 including those that originate from the host (comorbidities and coinfections) as well as those arising from the environment (e.g., zoonotic exposures), economic inequality (e.g. healthcare disparities), stigma (a confounder of leprosy and TB for millennia), and historical neglect (a confounder in Native American Nations). This conference report summarizes select talks given at MHM9 highlighting recent research advances, as well as talks regarding the historic and ongoing impact of TB and other infectious diseases on Native American Nations, including those in Southwestern Alaska where the regional TB incidence rate is among the highest in the Western hemisphere.
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Affiliation(s)
- Abigail Marie Klever
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA
| | - Kathleen A Alexander
- Department of Fish and Wildlife Conservation, Virginia Tech, Blacksburg, VA, USA; CARACAL/Chobe Research Institute Kasane, Botswana
| | - Deepak Almeida
- Center for Tuberculosis Research, Johns Hopkins University, Baltimore, MD, USA
| | - Matthew Z Anderson
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA; Department of Microbiology, The Ohio State University, Columbus, OH, USA
| | | | - Gillian Beamer
- Host Pathogen Interactions and Population Health Program, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Paola Boggiatto
- Agricultural Research Service, United States Department of Agriculture, Ames, IA, USA
| | - Jane E Buikstra
- Center for Bioarchaeological Research, Arizona State University, Tempe, AZ, USA
| | - Bruce Chandler
- Division of Public Health, Alaska Department of Health, AK, USA
| | - Tiffany A Claeys
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA
| | - Aislinn E Concha
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA
| | - Paul J Converse
- Center for Tuberculosis Research, Johns Hopkins University, Baltimore, MD, USA
| | - Keith M Derbyshire
- Division of Genetics, The Wadsworth Center, New York State Department of Health, Albany, NY, USA; Department of Biomedical Sciences, University at Albany, Albany, NY, USA
| | - Karen M Dobos
- Department of Microbiology, Immunology, and Pathology, Mycobacteria Research Laboratories, Colorado State University, Fort Collins, CO, USA
| | - Kathryn M Dupnik
- Center for Global Health, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Janice J Endsley
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
| | - Mark A Endsley
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
| | - Kevin Fennelly
- Pulmonary Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, MD, USA
| | - Carlos Franco-Paredes
- Department of Microbiology, Immunology, and Pathology, Mycobacteria Research Laboratories, Colorado State University, Fort Collins, CO, USA; Hospital Infantil de México Federico Gómez, México, USA
| | | | - Luanne Hall-Stoodley
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA
| | - Don Hayes
- Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | | | - Courtney A Hofman
- Department of Anthropology, University of Oklahoma, Norman, OK, USA; Laboratories of Molecular Anthropology and Microbiome Research, University of Oklahoma, Norman, OK, USA
| | - Jennifer R Honda
- Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, TX, USA
| | - Natalie M Hull
- Department of Civil, Environmental, and Geodetic Engineering, The Ohio State University, Columbus, OH, USA
| | - Igor Kramnik
- Pulmonary Center, The Department of Medicine, Boston University Chobanian & Aveedisian School of Medicine, National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA
| | - Karen Lacourciere
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
| | - Ramanuj Lahiri
- United States Department of Health and Human Services, Health Resources and Services Administration, Health Systems Bureau, National Hansen's Disease Program, Baton Rouge, LA, USA
| | - Elise A Lamont
- Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, USA
| | - Michelle H Larsen
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
| | | | - Sandrine Lesellier
- French Agency for Food, Environmental & Occupational Health & Safety (ANSES), Laboratory for Rabies and Wildlife,Nancy, France
| | - Naomi R Lee
- Department of Chemistry and Biochemistry, Northern Arizona University, Flagstaff, AZ, USA
| | - Christopher A Lowry
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA
| | - Najmus S Mahfooz
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA
| | - Temet M McMichael
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA
| | - Marlena R Merling
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA
| | - Michele A Miller
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Jyothi F Nagajyothi
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA
| | - Elizabeth Nelson
- Microbial Paleogenomics Unit, Dept of Genomes and Genetics, Institut Pasteur, Paris, France
| | - Eric L Nuermberger
- Center for Tuberculosis Research, Johns Hopkins University, Baltimore, MD, USA
| | - Maria T Pena
- United States Department of Health and Human Services, Health Resources and Services Administration, Health Systems Bureau, National Hansen's Disease Program, Baton Rouge, LA, USA
| | - Claudia Perea
- Animal & Plant Health Inspection Service, United States Department of Agriculture, Ames, IA, USA
| | - Brendan K Podell
- Department of Microbiology, Immunology, and Pathology, Mycobacteria Research Laboratories, Colorado State University, Fort Collins, CO, USA
| | - Charlie J Pyle
- Department of Molecular Genetics & Microbiology, Duke University School of Medicine, Durham, NC, USA; Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Fred D Quinn
- Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
| | - Murugesan V S Rajaram
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA
| | - Oscar Rosas Mejia
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA
| | | | - Saydie A Sago
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA
| | - Liliana C M Salvador
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, USA
| | - Andrew W Simonson
- Department of Microbiology and Molecular Genetics and the Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - John S Spencer
- Department of Microbiology, Immunology, and Pathology, Mycobacteria Research Laboratories, Colorado State University, Fort Collins, CO, USA
| | - Srinand Sreevatsan
- Pathobiology & Diagnostic Investigation Department, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
| | - Selvakumar Subbian
- Public Health Research Institute (PHRI), New Jersey Medical School, Rutgers University, Newark, NJ, USA
| | | | - David M Tobin
- Department of Molecular Genetics & Microbiology, Duke University School of Medicine, Durham, NC, USA; Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - K K Vidya Vijayan
- Department of Microbiology and Immunology, Center for AIDS Research, and Children's Research Institute, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Caelan T O Wright
- Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA
| | - Richard T Robinson
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Infectious Diseases Institute, The Ohio State University, OH, USA.
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Pelosi U, Pintus R, Savasta S, Fanos V. Pulmonary Tuberculosis in Children: A Forgotten Disease? Microorganisms 2023; 11:1722. [PMID: 37512894 PMCID: PMC10385511 DOI: 10.3390/microorganisms11071722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 06/20/2023] [Accepted: 06/26/2023] [Indexed: 07/30/2023] Open
Abstract
Even today, tuberculosis in childhood is a disease that is often undiagnosed and undertreated. In the absence of therapy with antituberculosis drugs, children in the first years of life have a high degree of severe forms and mortality. In these children, symptoms are often not very specific and can easily be confused with other diseases of bacterial, viral or fungal etiology, making diagnosis more difficult. Nevertheless, the introduction of new diagnostic techniques has allowed a more rapid identification of the infection. Indeed, Interferon gamma release assay (IGRA) is preferred to the Mantoux, albeit with obvious limitations in children aged <2 years. While the Xpert Mtb/RIF Ultra test is recommended as an initial diagnostic investigation of the gastric aspirate and/or stools in children with signs and symptoms of pulmonary tuberculosis. The drugs used in the treatment of susceptible and resistant TB are the same as those used in adults but doses and combinations are different in the pediatric age. In children, brief therapy is preferable in both the latent infection and the active disease, as a significant reduction in side effects is obtained.
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Affiliation(s)
- Umberto Pelosi
- Pediatric Unit, Santa Barbara Hospital, 09016 Iglesias, Italy
| | - Roberta Pintus
- Neonatal Intensive Care Unit, Department of Surgical Sciences, University of Cagliari, AOU Cagliari, 09124 Cagliari, Italy
| | - Salvatore Savasta
- Department of Pediatrics and Rare Diseases, Ospedale Microcitemico Antonio Cao, University of Cagliari, 09124 Cagliari, Italy
| | - Vassilios Fanos
- Neonatal Intensive Care Unit, Department of Surgical Sciences, University of Cagliari, AOU Cagliari, 09124 Cagliari, Italy
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15
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Kayongo A, Nyiro B, Siddharthan T, Kirenga B, Checkley W, Lutaakome Joloba M, Ellner J, Salgame P. Mechanisms of lung damage in tuberculosis: implications for chronic obstructive pulmonary disease. Front Cell Infect Microbiol 2023; 13:1146571. [PMID: 37415827 PMCID: PMC10320222 DOI: 10.3389/fcimb.2023.1146571] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 06/05/2023] [Indexed: 07/08/2023] Open
Abstract
Pulmonary tuberculosis is increasingly recognized as a risk factor for COPD. Severe lung function impairment has been reported in post-TB patients. Despite increasing evidence to support the association between TB and COPD, only a few studies describe the immunological basis of COPD among TB patients following successful treatment completion. In this review, we draw on well-elaborated Mycobacterium tuberculosis-induced immune mechanisms in the lungs to highlight shared mechanisms for COPD pathogenesis in the setting of tuberculosis disease. We further examine how such mechanisms could be exploited to guide COPD therapeutics.
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Affiliation(s)
- Alex Kayongo
- Department of Medicine, Center for Emerging Pathogens, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States
- Department of Immunology and Molecular Biology, College of Health Sciences, Makerere University, Kampala, Uganda
- Makerere University College of Health Sciences, Lung Institute, Makerere University, Kampala, Uganda
| | - Brian Nyiro
- Department of Medicine, Center for Emerging Pathogens, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States
- Department of Immunology and Molecular Biology, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Trishul Siddharthan
- Division of Pulmonary and Critical Care Medicine, University of Miami, Miami, FL, United States
| | - Bruce Kirenga
- Makerere University College of Health Sciences, Lung Institute, Makerere University, Kampala, Uganda
| | - William Checkley
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States
- Center for Global Non-Communicable Disease Research and Training, School of Medicine, Johns Hopkins University, Baltimore, MD, United States
| | - Moses Lutaakome Joloba
- Makerere University College of Health Sciences, Lung Institute, Makerere University, Kampala, Uganda
| | - Jerrold Ellner
- Department of Medicine, Center for Emerging Pathogens, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States
| | - Padmini Salgame
- Department of Medicine, Center for Emerging Pathogens, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States
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16
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Putera I, Schrijver B, Ten Berge JCEM, Gupta V, La Distia Nora R, Agrawal R, van Hagen PM, Rombach SM, Dik WA. The immune response in tubercular uveitis and its implications for treatment: From anti-tubercular treatment to host-directed therapies. Prog Retin Eye Res 2023:101189. [PMID: 37236420 DOI: 10.1016/j.preteyeres.2023.101189] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/23/2023] [Accepted: 05/24/2023] [Indexed: 05/28/2023]
Abstract
Tubercular uveitis (TB-uveitis) remains a conundrum in the uveitis field, which is mainly related to the diverse clinical phenotypes of TB-uveitis. Moreover, it remains difficult to differentiate whether Mycobacterium tuberculosis (Mtb) is present in the ocular tissues, elicits a heightened immune response without Mtb invasion in ocular tissues, or even induces an anti-retinal autoimmune response. Gaps in the immuno-pathological knowledge of TB-uveitis likely delay timely diagnosis and appropriate management. In the last decade, the immunopathophysiology of TB-uveitis and its clinical management, including experts' consensus to treat or not to treat certain conditions with anti-tubercular treatment (ATT), have been extensively investigated. In the meantime, research on TB treatment, in general, is shifting more toward host-directed therapies (HDT). Given the complexities of the host-Mtb interaction, enhancement of the host immune response is expected to boost the effectiveness of ATT and help overcome the rising burden of drug-resistant Mtb strains in the population. This review will summarize the current knowledge on the immunopathophysiology of TB-uveitis and recent advances in treatment modalities and outcomes of TB-uveitis, capturing results gathered from high- and low-burden TB countries with ATT as the mainstay of treatment. Moreover, we outline the recent progress of HDT development in the pulmonary TB field and discuss the possibility of its applicability to TB-uveitis. The concept of HDT might help direct future development of efficacious therapy for TB-uveitis, although more in-depth research on the immunoregulation of this disease is still necessary.
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Affiliation(s)
- Ikhwanuliman Putera
- Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Section Allergy and Clinical Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands; Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Ophthalmology, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia.
| | - Benjamin Schrijver
- Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | | | - Vishali Gupta
- Retina and Uvea Services, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Rina La Distia Nora
- Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Ophthalmology, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Rupesh Agrawal
- National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Ophthalmology and Visual Sciences Academic Clinical Program, Duke NUS University, Singapore; Singapore Eye Research Institute, Singapore; Moorfields Eye Hospital, London, United Kingdom
| | - P Martin van Hagen
- Department of Internal Medicine, Section Allergy and Clinical Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands; Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - S M Rombach
- Department of Internal Medicine, Section Allergy and Clinical Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Willem A Dik
- Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands
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17
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Fleeman R. Repurposing Inhibitors of Phosphoinositide 3-kinase as Adjuvant Therapeutics for Bacterial Infections. FRONTIERS IN ANTIBIOTICS 2023; 2:1135485. [PMID: 38983593 PMCID: PMC11233138 DOI: 10.3389/frabi.2023.1135485] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 01/30/2023] [Indexed: 07/11/2024]
Abstract
The rise in antimicrobial resistance and the decline in new antibiotics has created a great need for novel approaches to treat drug resistant bacterial infections. Increasing the burden of antimicrobial resistance, bacterial virulence factors allow for survival within the host, where they can evade host killing and antimicrobial therapy within their intracellular niches. Repurposing host directed therapeutics has great potential for adjuvants to allow for more effective bacterial killing by the host and antimicrobials. To this end, phosphoinositide 3-kinase inhibitors are FDA approved for cancer therapy, but also have potential to eliminate intracellular survival of pathogens. This review describes the PI3K pathway and its potential as an adjuvant target to treat bacterial infections more effectively.
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18
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Okugbeni N, du Toit A, Cole-Holman V, Johnson G, Loos B, Kinnear C. Measurement of Autophagy Activity Reveals Time-Dependent, Bacteria-Specific Turnover during Mycobacterium tuberculosis Infection. Pathogens 2022; 12:pathogens12010024. [PMID: 36678372 PMCID: PMC9864524 DOI: 10.3390/pathogens12010024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022] Open
Abstract
The intracellular pathogen, Mycobacterium tuberculosis (M. tb) uses various mechanisms to evade its killing. One of such is phagosomal damage and cytosolic translocation which is then targeted by the host's bactericidal autophagy pathway. It is suggested that cytosolic translocation of M. tb is time-dependent, occurring at later time points of 48 to 72 h post-infection. It is, however, not known whether increased autophagic targeting correlates with these time points of infection. We investigated the time-dependent profile of autophagy activity through the course of M. tb infection in mammalian macrophages. Autophagy activity was inferred by the turnover measurement of autophagy markers and M. tb bacilli in THP-1 and RAW 264.7 macrophages. Over a period of 4 to 72 h, we observed highest autophagy turnover at 48 h of infection in M. tb-containing cells. This was evident by the highest turnover levels of p62 and intracellular M. tb. This supports observations of phagosomal damage mostly occurring at this time point and reveal the correlation of increased autophagy activity. The findings support the preservation of autophagy activity despite M. tb infection while also highlighting time-dependent differences in M. tb-infected macrophages. Future studies may explore time-dependent exogenous autophagy targeting towards host-directed anti-tuberculosis therapy.
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Affiliation(s)
- Naomi Okugbeni
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, US/SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa
- South African Medical Research Council Genomics Centre, Tygerberg 7505, South Africa
| | - André du Toit
- Neuro Research Group, Department of Physiological Sciences, Faculty of Sciences, Stellenbosch University, Stellenbosch 7602, South Africa
| | - Victoria Cole-Holman
- South African Medical Research Council Genomics Centre, Tygerberg 7505, South Africa
| | - Glynis Johnson
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, US/SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa
| | - Ben Loos
- Neuro Research Group, Department of Physiological Sciences, Faculty of Sciences, Stellenbosch University, Stellenbosch 7602, South Africa
| | - Craig Kinnear
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, US/SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa
- South African Medical Research Council Genomics Centre, Tygerberg 7505, South Africa
- Correspondence:
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19
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Lee YJ, Kim JK, Jung CH, Kim YJ, Jung EJ, Lee SH, Choi HR, Son YS, Shim SM, Jeon SM, Choe JH, Lee SH, Whang J, Sohn KC, Hur GM, Kim HT, Yeom J, Jo EK, Kwon YT. Chemical modulation of SQSTM1/p62-mediated xenophagy that targets a broad range of pathogenic bacteria. Autophagy 2022; 18:2926-2945. [PMID: 35316156 PMCID: PMC9673928 DOI: 10.1080/15548627.2022.2054240] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
The N-degron pathway is a proteolytic system in which the N-terminal degrons (N-degrons) of proteins, such as arginine (Nt-Arg), induce the degradation of proteins and subcellular organelles via the ubiquitin-proteasome system (UPS) or macroautophagy/autophagy-lysosome system (hereafter autophagy). Here, we developed the chemical mimics of the N-degron Nt-Arg as a pharmaceutical means to induce targeted degradation of intracellular bacteria via autophagy, such as Salmonella enterica serovar Typhimurium (S. Typhimurium), Escherichia coli, and Streptococcus pyogenes as well as Mycobacterium tuberculosis (Mtb). Upon binding the ZZ domain of the autophagic cargo receptor SQSTM1/p62 (sequestosome 1), these chemicals induced the biogenesis and recruitment of autophagic membranes to intracellular bacteria via SQSTM1, leading to lysosomal degradation. The antimicrobial efficacy was independent of rapamycin-modulated core autophagic pathways and synergistic with the reduced production of inflammatory cytokines. In mice, these drugs exhibited antimicrobial efficacy for S. Typhimurium, Bacillus Calmette-Guérin (BCG), and Mtb as well as multidrug-resistant Mtb and inhibited the production of inflammatory cytokines. This dual mode of action in xenophagy and inflammation significantly protected mice from inflammatory lesions in the lungs and other tissues caused by all the tested bacterial strains. Our results suggest that the N-degron pathway provides a therapeutic target in host-directed therapeutics for a broad range of drug-resistant intracellular pathogens.Abbreviations: ATG: autophagy-related gene; BCG: Bacillus Calmette-Guérin; BMDMs: bone marrow-derived macrophages; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CFUs: colony-forming units; CXCL: C-X-C motif chemokine ligand; EGFP: enhanced green fluorescent protein; IL1B/IL-1β: interleukin 1 beta; IL6: interleukin 6; LIR: MAP1LC3/LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; Mtb: Mycobacterium tuberculosis; MTOR: mechanistic target of rapamycin kinase; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PB1: Phox and Bem1; SQSTM1/p62: sequestosome 1; S. Typhimurium: Salmonella enterica serovar Typhimurium; TAX1BP1: Tax1 binding protein 1; TNF: tumor necrosis factor; UBA: ubiquitin-associated.
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Affiliation(s)
- Yoon Jee Lee
- Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Jin Kyung Kim
- Department of Microbiology, Chungnam National University School of Medicine, Daejeon, Korea,Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Korea,Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, Korea
| | - Chan Hoon Jung
- Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Young Jae Kim
- Department of Microbiology, Chungnam National University School of Medicine, Daejeon, Korea,Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Korea,Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, Korea
| | - Eui Jung Jung
- Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Su Hyun Lee
- Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Ha Rim Choi
- Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Yeon Sung Son
- Neuroscience Research Institute, Medical Research Center, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Sang Mi Shim
- Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Sang Min Jeon
- Department of Microbiology, Chungnam National University School of Medicine, Daejeon, Korea,Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Korea,Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, Korea
| | - Jin Ho Choe
- Department of Microbiology, Chungnam National University School of Medicine, Daejeon, Korea,Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Korea,Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, Korea
| | - Sang-Hee Lee
- Center for Research Equipment, Korea Basic Science Institute, Cheongju, Korea
| | - Jake Whang
- Korea Mycobacterium Resource Center (KMRC) & Basic Research Section, The Korean Institute of Tuberculosis (KIT), Cheongju, Korea
| | - Kyung-Cheol Sohn
- Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Korea,Department of Pharmacology, Chungnam National University School of Medicine, Daejeon, Korea
| | - Gang Min Hur
- Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Korea,Department of Pharmacology, Chungnam National University School of Medicine, Daejeon, Korea
| | - Hyun Tae Kim
- Chemistry R&D Center, AUTOTAC Bio Inc, Seoul, Republic of Korea
| | - Jinki Yeom
- Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea,Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Eun-Kyeong Jo
- Department of Microbiology, Chungnam National University School of Medicine, Daejeon, Korea,Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Korea,Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, Korea,CONTACT Eun-Kyeong Jo Department of Microbiology, and Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon35015, Korea
| | - Yong Tae Kwon
- Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea,Chemistry R&D Center, AUTOTAC Bio Inc, Seoul, Republic of Korea,SNU Dementia Research Center, College of Medicine, Seoul National University, Seoul, Republic of Korea,Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul, Republic of Korea,Yong Tae Kwon Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul110-799, Korea
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20
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Dasmahapatra U, Chanda K. Synthetic approaches to potent heterocyclic inhibitors of tuberculosis: A decade review. Front Pharmacol 2022; 13:1021216. [PMID: 36386156 PMCID: PMC9661889 DOI: 10.3389/fphar.2022.1021216] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 10/03/2022] [Indexed: 09/08/2024] Open
Abstract
Tuberculosis (TB) continues to be a significant global health concern with about 1.5 million deaths annually. Despite efforts to develop more efficient vaccines, reliable diagnostics, and chemotherapeutics, tuberculosis has become a concern to world health due to HIV, the rapid growth of bacteria that are resistant to treatment, and the recently introduced COVID-19 pandemic. As is well known, advances in synthetic organic chemistry have historically enabled the production of important life-saving medications that have had a tremendous impact on patients' lives and health all over the world. Small-molecule research as a novel chemical entity for a specific disease target offers in-depth knowledge and potential therapeutic targets. In this viewpoint, we concentrated on the synthesis of a number of heterocycles reported in the previous decade and the screening of their inhibitory action against diverse strains of Mycobacterium tuberculosis. These findings offer specific details on the structure-based activity of several heterocyclic scaffolds backed by their in vitro tests as a promising class of antitubercular medicines, which will be further useful to build effective treatments to prevent this terrible illness.
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Affiliation(s)
| | - Kaushik Chanda
- Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore, India
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21
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Bahlool AZ, Fattah S, O’Sullivan A, Cavanagh B, MacLoughlin R, Keane J, O’Sullivan MP, Cryan SA. Development of Inhalable ATRA-Loaded PLGA Nanoparticles as Host-Directed Immunotherapy against Tuberculosis. Pharmaceutics 2022; 14:pharmaceutics14081745. [PMID: 36015371 PMCID: PMC9415714 DOI: 10.3390/pharmaceutics14081745] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/11/2022] [Accepted: 08/20/2022] [Indexed: 11/16/2022] Open
Abstract
Developing new effective treatment strategies to overcome the rise in multi-drug resistant tuberculosis cases (MDR-TB) represents a global challenge. A host-directed therapy (HDT), acting on the host immune response rather than Mtb directly, could address these resistance issues. We developed an HDT for targeted TB treatment, using All Trans Retinoic Acid (ATRA)-loaded nanoparticles (NPs) that are suitable for nebulization. Efficacy studies conducted on THP-1 differentiated cells infected with the H37Ra avirulent Mycobacterium tuberculosis (Mtb) strain, have shown a dose-dependent reduction in H37Ra growth as determined by the BACT/ALERT® system. Confocal microscopy images showed efficient and extensive cellular delivery of ATRA-PLGA NPs into THP-1-derived macrophages. A commercially available vibrating mesh nebulizer was used to generate nanoparticle-loaded droplets with a mass median aerodynamic diameter of 2.13 μm as measured by cascade impaction, and a volumetric median diameter of 4.09 μm as measured by laser diffraction. In an adult breathing simulation experiment, 65.1% of the ATRA PLGA-NP dose was inhaled. This targeted inhaled HDT could offer a new adjunctive TB treatment option that could enhance current dosage regimens leading to better patient prognosis and a decreasing incidence of MDR-TB.
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Affiliation(s)
- Ahmad Z. Bahlool
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, D02 YN77 Dublin, Ireland
- Tissue Engineering Research Group, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, D02 YN77 Dublin, Ireland
- Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College Dublin, The University of Dublin, D08 9WRT Dublin, Ireland
| | - Sarinj Fattah
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, D02 YN77 Dublin, Ireland
- Tissue Engineering Research Group, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, D02 YN77 Dublin, Ireland
| | - Andrew O’Sullivan
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, D02 YN77 Dublin, Ireland
- Research and Development, Science and Emerging Technologies, Aerogen Ltd., Galway Business Park, Dangan, H91 HE94 Galway, Ireland
| | - Brenton Cavanagh
- Cellular and Molecular Imaging Core, Royal College of Surgeons in Ireland RCSI, D02 YN77 Dublin, Ireland
| | - Ronan MacLoughlin
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, D02 YN77 Dublin, Ireland
- Research and Development, Science and Emerging Technologies, Aerogen Ltd., Galway Business Park, Dangan, H91 HE94 Galway, Ireland
- School of Pharmacy and Pharmaceutical Sciences, Trinity College, D02 PN40 Dublin, Ireland
| | - Joseph Keane
- Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College Dublin, The University of Dublin, D08 9WRT Dublin, Ireland
| | - Mary P. O’Sullivan
- Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College Dublin, The University of Dublin, D08 9WRT Dublin, Ireland
| | - Sally-Ann Cryan
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, D02 YN77 Dublin, Ireland
- Tissue Engineering Research Group, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, D02 YN77 Dublin, Ireland
- SFI Advanced Materials and Bioengineering Research (AMBER) Centre, RCSI and Trinity College Dublin, D02 PN40 Dublin, Ireland
- SFI Centre for Research in Medical Devices (CÚRAM), NUIG & RCSI, H91 W2TY Galway, Ireland
- Correspondence:
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22
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Davuluri KS, Singh AK, Kumar V, Singh SV, Singh AV, Kumar S, Yadav R, Kushwaha S, Chauhan DS. Stimulated expression of ELR+ chemokines, VEGFA and TNF-AIP3 promote mycobacterial dissemination in extrapulmonary tuberculosis patients and Cavia porcellus model of tuberculosis. Tuberculosis (Edinb) 2022; 135:102224. [PMID: 35763913 DOI: 10.1016/j.tube.2022.102224] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 06/06/2022] [Accepted: 06/12/2022] [Indexed: 11/16/2022]
Abstract
Pathogenic mycobacteria induce and accelerate blood vessel formation driven by extensive inflammation during granuloma formation, which is a central feature of mycobacterial pathogenesis. Tumor necrosis factor-alpha (TNF-α) enhances the expression of vascular endothelial growth factor (VEGF) and glutamic acid-leucine-arginine (ELR+) chemokines, which are potent inducers of vascularization. Most of the reported research work contends that VEGF growth factor induces neovascularization in human tuberculosis (TB) patients, but the evidence is inconclusive. Considerable ambiguity exists concerning the factors responsible for miliary tuberculosis. To identify such factors, we proposed an alternative explanation that could be found in miliary tuberculosis (MTB) cases. We performed a comparative analysis of angiogenic factors TNF-α, VEGF, and angiogenic ELR+ CXC and CC chemokine ligands in extrapulmonary tuberculosis (EPTB) and pulmonary tuberculosis (PTB) patients. To observe the relationship of these factors with the severity of bacterial burden, guinea pigs were infected with Mycobacterium tuberculosis (M.tb) and levels of the angiogenic factors were examined at different time intervals. Expression of these factors also exhibited a significant positive correlation with bacterial burden in other organs like the spleen, liver, and lymph nodes. We demonstrated statistical data on bacterial burden at different time points following the dissemination of infection in guinea pigs. In this study, we observed that there was a stimulated increase in the expression of ELR+ chemokines and VEGF in EPTB patients as compared to PTB patients. Following increased dissemination, the host immune response clears bacteria from the lungs during disease progression in guinea pigs.
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Affiliation(s)
- Kusuma Sai Davuluri
- Department of Microbiology and Molecular Biology, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra, 282001, India.
| | - Amit Kumar Singh
- Department of Animal Experimentation and Facility, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra, 281406, India.
| | - Vimal Kumar
- Department of Animal Experimentation and Facility, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra, 281406, India.
| | - Shoor Vir Singh
- Department of Biotechnology, GLA University, Mathura, 281406, India.
| | - Ajay Vir Singh
- Department of Microbiology and Molecular Biology, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra, 282001, India.
| | - Santhosh Kumar
- Department of Pulmonary Medicine, SNMC, Agra, 282001, India
| | - Rajbala Yadav
- Department of Microbiology and Molecular Biology, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra, 282001, India
| | - Shweta Kushwaha
- Department of Microbiology and Molecular Biology, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra, 282001, India
| | - Devendra Singh Chauhan
- Department of Microbiology and Molecular Biology, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra, 282001, India.
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23
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Gairola A, Benjamin A, Weatherston JD, Cirillo JD, Wu HJ. Recent Developments in Drug Delivery for Treatment of Tuberculosis by Targeting Macrophages. ADVANCED THERAPEUTICS 2022; 5:2100193. [PMID: 36203881 PMCID: PMC9531895 DOI: 10.1002/adtp.202100193] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Indexed: 11/10/2022]
Abstract
Tuberculosis (TB) is among the greatest public health and safety concerns in the 21st century, Mycobacterium tuberculosis, which causes TB, infects alveolar macrophages and uses these cells as one of its primary sites of replication. The current TB treatment regimen, which consist of chemotherapy involving a combination of 3-4 antimicrobials for a duration of 6-12 months, is marked with significant side effects, toxicity, and poor compliance. Targeted drug delivery offers a strategy that could overcome many of the problems of current TB treatment by specifically targeting infected macrophages. Recent advances in nanotechnology and material science have opened an avenue to explore drug carriers that actively and passively target macrophages. This approach can increase the drug penetration into macrophages by using ligands on the nanocarrier that interact with specific receptors for macrophages. This review encompasses the recent development of drug carriers specifically targeting macrophages actively and passively. Future directions and challenges associated with development of effective TB treatment is also discussed.
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Affiliation(s)
- Anirudh Gairola
- Department of Chemical Engineering, Texas A&M University, College Station, Texas, USA
| | - Aaron Benjamin
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, Texas, USA
| | - Joshua D Weatherston
- Department of Chemical Engineering, Texas A&M University, College Station, Texas, USA
| | - Jeffrey D Cirillo
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, Texas, USA
| | - Hung-Jen Wu
- Department of Chemical Engineering, Texas A&M University, College Station, Texas, USA
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24
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A century of attempts to develop an effective tuberculosis vaccine: Why they failed? Int Immunopharmacol 2022; 109:108791. [PMID: 35487086 DOI: 10.1016/j.intimp.2022.108791] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 04/18/2022] [Accepted: 04/18/2022] [Indexed: 11/23/2022]
Abstract
Tuberculosis (TB) remains a major global health problem despite widespread use of the Bacillus BCG vaccine. This situation is worsened by co-infection with HIV, and the development of multidrug-resistant Mycobacterium tuberculosis (Mtb) strains. Thus, novel vaccine candidates and improved vaccination strategies are urgently needed in order to reduce the incidence of TB and even to eradicate TB by 2050. Over the last few decades, 23 novel TB vaccines have entered into clinical trials, more than 13 new vaccines have reached various stages of preclinical development, and more than 50 potential candidates are in the discovery stage as next-generation vaccines. Nevertheless, why has a century of attempts to introduce an effective TB vaccine failed? Who should be blamed -scientists, human response, or Mtb strategies? Literature review reveals that the elimination of latent or active Mtb infections in a given population seems to be an epigenetic process. With a better understanding of the connections between bacterial infections and gene expression conditions in epigenetic events, opportunities arise in designing protective vaccines or therapeutic agents, particularly as epigenetic processes can be reversed. Therefore, this review provides a brief overview of different approaches towards novel vaccination strategies and the mechanisms underlying these approaches.
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25
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Bahlool AZ, Grant C, Cryan SA, Keane J, O'Sullivan MP. All trans retinoic acid as a host-directed immunotherapy for tuberculosis. CURRENT RESEARCH IN IMMUNOLOGY 2022; 3:54-72. [PMID: 35496824 PMCID: PMC9040133 DOI: 10.1016/j.crimmu.2022.03.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 03/11/2022] [Accepted: 03/22/2022] [Indexed: 12/22/2022] Open
Abstract
Tuberculosis (TB) is the top bacterial infectious disease killer and one of the top ten causes of death worldwide. The emergence of strains of multiple drug-resistant tuberculosis (MDR-TB) has pushed our available stock of anti-TB agents to the limit of effectiveness. This has increased the urgent need to develop novel treatment strategies using currently available resources. An adjunctive, host-directed therapy (HDT) designed to act on the host, instead of the bacteria, by boosting the host immune response through activation of intracellular pathways could be the answer. The integration of multidisciplinary approaches of repurposing currently FDA-approved drugs, with a targeted drug-delivery platform is a very promising option to reduce the long timeline associated with the approval of new drugs - time that cannot be afforded given the current levels of morbidity and mortality associated with TB infection. The deficiency of vitamin A has been reported to be highly associated with the increased susceptibility of TB. All trans retinoic acid (ATRA), the active metabolite of vitamin A, has proven to be very efficacious against TB both in vitro and in vivo. In this review, we discuss and summarise the importance of vitamin A metabolites in the fight against TB and what is known regarding the molecular mechanisms of ATRA as a host-directed therapy for TB including its effect on macrophages cytokine profile and cellular pathways. Furthermore, we focus on the issues behind why previous clinical trials with vitamin A supplementation have failed, and how these issues might be overcome.
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Affiliation(s)
- Ahmad Z. Bahlool
- School of Pharmacy and Biomolecular Sciences (PBS), Royal College of Surgeons in Ireland (RCSI), 123 St Stephens Green, Dublin 2, Ireland
- Tissue Engineering Research Group (TERG), Royal College of Surgeons in Ireland (RCSI), 123 St Stephens Green, Dublin 2, Ireland
- Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, Ireland
| | - Conor Grant
- Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, Ireland
| | - Sally-Ann Cryan
- School of Pharmacy and Biomolecular Sciences (PBS), Royal College of Surgeons in Ireland (RCSI), 123 St Stephens Green, Dublin 2, Ireland
- Tissue Engineering Research Group (TERG), Royal College of Surgeons in Ireland (RCSI), 123 St Stephens Green, Dublin 2, Ireland
- SFI Advanced Materials and Bioengineering Research (AMBER) Centre, RCSI & TCD, Dublin, Ireland
- SFI Centre for Research in Medical Devices (CURAM), RCSI, Dublin and National University of Ireland, Galway, Ireland
| | - Joseph Keane
- Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, Ireland
| | - Mary P. O'Sullivan
- Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, Ireland
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Sui J, Qiao W, Xiang X, Luo Y. Epigenetic Changes in Mycobacterium tuberculosis and its Host Provide Potential Targets or Biomarkers for Drug Discovery and Clinical Diagnosis. Pharmacol Res 2022; 179:106195. [DOI: 10.1016/j.phrs.2022.106195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 03/14/2022] [Accepted: 03/25/2022] [Indexed: 11/26/2022]
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27
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Feng W, Li G, Kang X, Wang R, Liu F, Zhao D, Li H, Bu F, Yu Y, Moriarty TF, Ren Q, Wang X. Cascade-Targeting Poly(amino acid) Nanoparticles Eliminate Intracellular Bacteria via On-Site Antibiotic Delivery. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2109789. [PMID: 35066925 DOI: 10.1002/adma.202109789] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/13/2022] [Indexed: 06/14/2023]
Abstract
Intracellular bacteria in latent or dormant states tolerate high-dose antibiotics. Fighting against these opportunistic bacteria has been a long-standing challenge. Herein, the design of a cascade-targeting drug delivery system (DDS) that can sequentially target macrophages and intracellular bacteria, exhibiting on-site drug delivery, is reported. The DDS is fabricated by encapsulating rifampicin (Rif) into mannose-decorated poly(α-N-acryloyl-phenylalanine)-block-poly(β-N-acryloyl-d-aminoalanine) nanoparticles, denoted as Rif@FAM NPs. The mannose units on Rif@FAM NPs guide the initial macrophage-specific uptake and intracellular accumulation. After the uptake, the detachment of mannose in acidic phagolysosome via Schiff base cleavage exposes the d-aminoalanine moieties, which subsequently steer the NPs to escape from lysosomes and target intracellular bacteria through peptidoglycan-specific binding, as evidenced by the in situ/ex situ co-localization using confocal, flow cytometry, and transmission electron microscopy. Through the on-site Rif delivery, Rif@FAM NPs show superior in vitro and in vivo elimination efficiency than the control groups of free Rif or the DDSs lacking the macrophages- or bacteria-targeting moieties. Furthermore, Rif@FAM NPs remodel the innate immune response of the infected macrophages by upregulating M1/M2 polarization, resulting in a reinforced antibacterial capacity. Therefore, this biocompatible DDS enabling macrophages and bacteria targeting in a cascade manner provides a new outlook for the therapy of intracellular pathogen infection.
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Affiliation(s)
- Wenli Feng
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, P. R. China
| | - Guofeng Li
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, P. R. China
| | - Xiaoxu Kang
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, P. R. China
| | - Ruibai Wang
- State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, P. R. China
| | - Fang Liu
- Department of Oncology of Integrative Chinese and Western Medicine, China-Japan Friendship Hospital, Beijing, 100029, P. R. China
| | - Dongdong Zhao
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, P. R. China
| | - Haofei Li
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, P. R. China
| | - Fanqiang Bu
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, P. R. China
| | - Yingjie Yu
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, P. R. China
| | | | - Qun Ren
- Empa, the Swiss Federal Laboratories for Materials Science and Technology, Laboratory for Biointerfaces, Lerchenfeldstrasse 5, St. Gallen, 9014, Switzerland
| | - Xing Wang
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, P. R. China
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Zheng J, Long X, Chen H, Ji Z, Shu B, Yue R, Liao Y, Ma S, Qiao K, Liu Y, Liao Y. Photoclick Reaction Constructs Glutathione-Responsive Theranostic System for Anti-Tuberculosis. Front Mol Biosci 2022; 9:845179. [PMID: 35237665 PMCID: PMC8883117 DOI: 10.3389/fmolb.2022.845179] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 01/10/2022] [Indexed: 12/12/2022] Open
Abstract
Tuberculosis (TB) is a virulent form of an infectious disease that causes a global burden due to its high infectivity and fatality rate, especially the irrepressible threats of latent infection. Constructing an efficient strategy for the prevention and control of TB is of great significance. Fortunately, we found that granulomas are endowed with higher reducibility levels possibly caused by internal inflammation and a relatively enclosed microenvironment. Therefore, we developed the first targeted glutathione- (GSH-) responsive theranostic system (RIF@Cy5.5-HA-NG) for tuberculosis with a rifampicin- (RIF-) loaded near-infrared emission carrier, which was constructed by photoclick reaction-actuated hydrophobic-hydrophobic interaction, enabling the early diagnosis of tuberculosis through granulomas-tracking. Furthermore, the loaded rifampicin was released through the dissociation of disulfide bond by the localized GSH in granulomas, realizing the targeted tuberculosis therapy and providing an especially accurate treatment mapping for tuberculosis. Thus, this targeted theranostic strategy for tuberculosis exhibits the potential to realize both granulomas-tracking and anti-infection of tuberculosis.
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Affiliation(s)
- Judun Zheng
- Molecular Diagnosis and Treatment Center for Infectious Diseases, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Xun Long
- Department of Science and Education, The Third People’s Hospital of Bijie City, Bijie, China
| | - Hao Chen
- Division of Gastrointestinal Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhisheng Ji
- Department of Orthopedics, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Bowen Shu
- Molecular Diagnosis and Treatment Center for Infectious Diseases, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Rui Yue
- Molecular Diagnosis and Treatment Center for Infectious Diseases, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Yechun Liao
- Department of Science and Education, The Third People’s Hospital of Bijie City, Bijie, China
| | - Shengchao Ma
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, China
| | - Kun Qiao
- Department of Thoracic Surgery, Shenzhen Third People’s Hospital, Shenzhen, China
| | - Ying Liu
- Department of Science and Education, The Third People’s Hospital of Bijie City, Bijie, China
| | - Yuhui Liao
- Molecular Diagnosis and Treatment Center for Infectious Diseases, Dermatology Hospital, Southern Medical University, Guangzhou, China
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, China
- Department of Infectious Disease, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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29
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Perveen S, Kumari D, Singh K, Sharma R. Tuberculosis drug discovery: Progression and future interventions in the wake of emerging resistance. Eur J Med Chem 2022; 229:114066. [PMID: 34973508 DOI: 10.1016/j.ejmech.2021.114066] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 12/13/2021] [Accepted: 12/19/2021] [Indexed: 02/06/2023]
Abstract
The emergence of drug resistance continues to afflict TB control where drug resistant strains have become a global health concern. Contrary to drug-sensitive TB, the treatment of MDR/XDR-TB is more complicated requiring the administration of second-line drugs that are inefficient than the first line drugs and are associated with greater side effects. The emergence of drug resistant Mtb strains had coincided with an innovation void in the field of drug discovery of anti-mycobacterials. However, the approval of bedaquiline and delamanid recently for use in MDR/XDR-TB has given an impetus to the TB drug discovery. The review discusses the drug discovery efforts in the field of tuberculosis with a focus on the strategies adopted and challenges confronted by TB research community. Here, we discuss the diverse clinical candidates in the current TB drug discovery pipeline. There is an urgent need to combat the current TB menace through multidisciplinary approaches and strategies making use of the recent advances in understanding the molecular biology and pathogenesis of Mtb. The review highlights the recent advances in drug discovery, with the host directed therapeutics and nanoparticles-drug delivery coming up as important tools to fight tuberculosis in the future.
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Affiliation(s)
- Summaya Perveen
- Infectious Diseases Division, CSIR- Indian Institute of Integrative Medicine, Jammu, 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Diksha Kumari
- Infectious Diseases Division, CSIR- Indian Institute of Integrative Medicine, Jammu, 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Kuljit Singh
- Infectious Diseases Division, CSIR- Indian Institute of Integrative Medicine, Jammu, 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Rashmi Sharma
- Infectious Diseases Division, CSIR- Indian Institute of Integrative Medicine, Jammu, 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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30
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Guler R, Ozturk M, Sabeel S, Motaung B, Parihar SP, Thienemann F, Brombacher F. Targeting Molecular Inflammatory Pathways in Granuloma as Host-Directed Therapies for Tuberculosis. Front Immunol 2021; 12:733853. [PMID: 34745105 PMCID: PMC8563828 DOI: 10.3389/fimmu.2021.733853] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 10/01/2021] [Indexed: 01/15/2023] Open
Abstract
Globally, more than 10 million people developed active tuberculosis (TB), with 1.4 million deaths in 2020. In addition, the emergence of drug-resistant strains in many regions of the world threatens national TB control programs. This requires an understanding of host-pathogen interactions and finding novel treatments including host-directed therapies (HDTs) is of utter importance to tackle the TB epidemic. Mycobacterium tuberculosis (Mtb), the causative agent for TB, mainly infects the lungs causing inflammatory processes leading to immune activation and the development and formation of granulomas. During TB disease progression, the mononuclear inflammatory cell infiltrates which form the central structure of granulomas undergo cellular changes to form epithelioid cells, multinucleated giant cells and foamy macrophages. Granulomas further contain neutrophils, NK cells, dendritic cells and an outer layer composed of T and B lymphocytes and fibroblasts. This complex granulomatous host response can be modulated by Mtb to induce pathological changes damaging host lung tissues ultimately benefiting the persistence and survival of Mtb within host macrophages. The development of cavities is likely to enhance inter-host transmission and caseum could facilitate the dissemination of Mtb to other organs inducing disease progression. This review explores host targets and molecular pathways in the inflammatory granuloma host immune response that may be beneficial as target candidates for HDTs against TB.
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Affiliation(s)
- Reto Guler
- International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town, South Africa.,Department of Pathology, University of Cape Town, Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.,Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Mumin Ozturk
- International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town, South Africa.,Department of Pathology, University of Cape Town, Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Solima Sabeel
- International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town, South Africa.,Department of Pathology, University of Cape Town, Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Bongani Motaung
- International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town, South Africa.,Department of Pathology, University of Cape Town, Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Suraj P Parihar
- International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town, South Africa.,Department of Pathology, University of Cape Town, Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.,Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Friedrich Thienemann
- General Medicine & Global Health, Cape Heart Institute, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.,Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.,Department of Internal Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Frank Brombacher
- International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town, South Africa.,Department of Pathology, University of Cape Town, Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.,Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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31
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Llibre A, Dedicoat M, Burel JG, Demangel C, O’Shea MK, Mauro C. Host Immune-Metabolic Adaptations Upon Mycobacterial Infections and Associated Co-Morbidities. Front Immunol 2021; 12:747387. [PMID: 34630426 PMCID: PMC8495197 DOI: 10.3389/fimmu.2021.747387] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/08/2021] [Indexed: 12/14/2022] Open
Abstract
Mycobacterial diseases are a major public health challenge. Their causative agents include, in order of impact, members of the Mycobacterium tuberculosis complex (causing tuberculosis), Mycobacterium leprae (causing leprosy), and non-tuberculous mycobacterial pathogens including Mycobacterium ulcerans. Macrophages are mycobacterial targets and they play an essential role in the host immune response to mycobacteria. This review aims to provide a comprehensive understanding of the immune-metabolic adaptations of the macrophage to mycobacterial infections. This metabolic rewiring involves changes in glycolysis and oxidative metabolism, as well as in the use of fatty acids and that of metals such as iron, zinc and copper. The macrophage metabolic adaptations result in changes in intracellular metabolites, which can post-translationally modify proteins including histones, with potential for shaping the epigenetic landscape. This review will also cover how critical tuberculosis co-morbidities such as smoking, diabetes and HIV infection shape host metabolic responses and impact disease outcome. Finally, we will explore how the immune-metabolic knowledge gained in the last decades can be harnessed towards the design of novel diagnostic and therapeutic tools, as well as vaccines.
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Affiliation(s)
- Alba Llibre
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Martin Dedicoat
- Department of Infectious Diseases, Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Julie G. Burel
- Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, United States
| | - Caroline Demangel
- Immunobiology of Infection Unit, Institut Pasteur, INSERM U1224, Paris, France
| | - Matthew K. O’Shea
- Department of Infectious Diseases, Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Claudio Mauro
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
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32
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Mukundan S, Bhatt R, Lucas J, Tereyek M, Chang TL, Subbian S, Parekkadan B. 3D host cell and pathogen-based bioassay development for testing anti-tuberculosis (TB) drug response and modeling immunodeficiency. Biomol Concepts 2021; 12:117-128. [PMID: 34473918 DOI: 10.1515/bmc-2021-0013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 06/24/2021] [Indexed: 11/15/2022] Open
Abstract
Tuberculosis (TB) is a global health threat that affects 10 million people worldwide. Human Immunodeficiency Virus (HIV) remains one of the major contributors to the reactivation of asymptomatic latent tuberculosis (LTBI). Over the recent years, there has been a significant focus in developing in-vitro 3D models mimicking early events of Mycobacterium tuberculosis (Mtb) pathogenesis, especially formation of the granuloma. However, these models are low throughput and require extracellular matrix. In this article, we report the generation of a matrix-free 3D model, using THP-1 human monocyte/macrophage cells and mCherry-expressing Mycobacterium bovis BCG (Bacilli Camille Guérin), henceforth referred as 3D spheroids, to study the host cell-bacterial interactions. Using mCherry-intensity-based tracking, we monitored the kinetics of BCG growth in the 3D spheroids. We also demonstrate the application of the 3D spheroids for testing anti-TB compounds such as isoniazid (INH), rifampicin (RIF), as well as a host-directed drug, everolimus (EVR) as single and combinational treatments. We further established a dual infection 3D spheroid model by coinfecting THP-1 macrophages with BCG mCherry and pseudotype HIV. In this HIV-TB co-infection model, we found an increase in BCG mCherry growth within the 3D spheroids infected with HIV pseudotype. The degree of disruption of the granuloma was proportional to the virus titers used for co-infection. In summary, this 3D spheroid assay is an useful tool to screen anti-TB response of potential candidate drugs and can be adopted to model HIV-TB interactions.
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Affiliation(s)
- Shilpaa Mukundan
- Department of Biomedical Engineering, Rutgers, The State University of New Jersey, NJ 08854
| | - Rachana Bhatt
- Department of Biomedical Engineering, Rutgers, The State University of New Jersey, NJ 08854
| | - John Lucas
- Department of Biomedical Engineering, Rutgers, The State University of New Jersey, NJ 08854
| | - Matthew Tereyek
- Department of Biomedical Engineering, Rutgers, The State University of New Jersey, NJ 08854
| | - Theresa L Chang
- Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, NJ 07103
| | - Selvakumar Subbian
- Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, NJ 07103
| | - Biju Parekkadan
- Department of Biomedical Engineering, Rutgers, The State University of New Jersey, NJ 08854; Department of Medicine, Rutgers Biomedical Health Sciences, Rutgers, The State University of New Jersey, NJ 08854
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33
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Kotze LA, Beltran CGG, Lang D, Loxton AG, Cooper S, Meiring M, Koegelenberg CFN, Allwood BW, Malherbe ST, Hiemstra AM, Glanzmann B, Kinnear C, Walzl G, du Plessis N. Establishment of a Patient-Derived, Magnetic Levitation-Based, Three-Dimensional Spheroid Granuloma Model for Human Tuberculosis. mSphere 2021; 6:e0055221. [PMID: 34287004 PMCID: PMC8386456 DOI: 10.1128/msphere.00552-21] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 12/18/2022] Open
Abstract
Tuberculous granulomas that develop in response to Mycobacterium tuberculosis (M. tuberculosis) infection are highly dynamic entities shaped by the host immune response and disease kinetics. Within this microenvironment, immune cell recruitment, polarization, and activation are driven not only by coexisting cell types and multicellular interactions but also by M. tuberculosis-mediated changes involving metabolic heterogeneity, epigenetic reprogramming, and rewiring of the transcriptional landscape of host cells. There is an increased appreciation of the in vivo complexity, versatility, and heterogeneity of the cellular compartment that constitutes the tuberculosis (TB) granuloma and the difficulty in translating findings from animal models to human disease. Here, we describe a novel biomimetic in vitro three-dimensional (3D) human lung spheroid granuloma model, resembling early "innate" and "adaptive" stages of the TB granuloma spectrum, and present results of histological architecture, host transcriptional characterization, mycobacteriological features, cytokine profiles, and spatial distribution of key immune cells. A range of manipulations of immune cell populations in these spheroid granulomas will allow the study of host/pathogen pathways involved in the outcome of infection, as well as pharmacological interventions. IMPORTANCE TB is a highly infectious disease, with granulomas as its hallmark. Granulomas play an important role in the control of M. tuberculosis infection and as such are crucial indicators for our understanding of host resistance to TB. Correlates of risk and protection to M. tuberculosis are still elusive, and the granuloma provides the perfect environment in which to study the immune response to infection and broaden our understanding thereof; however, human granulomas are difficult to obtain, and animal models are costly and do not always faithfully mimic human immunity. In fact, most TB research is conducted in vitro on immortalized or primary immune cells and cultured in two dimensions on flat, rigid plastic, which does not reflect in vivo characteristics. We have therefore conceived a 3D, human in vitro spheroid granuloma model which allows researchers to study features of granuloma-forming diseases in a 3D structural environment resembling in vivo granuloma architecture and cellular orientation.
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Affiliation(s)
- Leigh A. Kotze
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Caroline G. G. Beltran
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Dirk Lang
- Confocal and Light Microscopy Imaging Facility, University of Cape Town, Cape Town, South Africa
| | - Andre G. Loxton
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Susan Cooper
- Confocal and Light Microscopy Imaging Facility, University of Cape Town, Cape Town, South Africa
| | - Maynard Meiring
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Coenraad F. N. Koegelenberg
- Division of Pulmonology, Department of Medicine, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa
| | - Brian W. Allwood
- Division of Pulmonology, Department of Medicine, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa
| | - Stephanus T. Malherbe
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Andriette M. Hiemstra
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Brigitte Glanzmann
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- South African Medical Research Council Genomics Centre, Cape Town, South Africa
| | - Craig Kinnear
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- South African Medical Research Council Genomics Centre, Cape Town, South Africa
| | - Gerhard Walzl
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Nelita du Plessis
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
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Kim YJ, Lee SH, Jeon SM, Silwal P, Seo JY, Hanh BTB, Park JW, Whang J, Lee MJ, Heo JY, Kim SH, Kim JM, Song GY, Jang J, Jo EK. Sirtuin 3 is essential for host defense against Mycobacterium abscessus infection through regulation of mitochondrial homeostasis. Virulence 2021; 11:1225-1239. [PMID: 32835604 PMCID: PMC7549921 DOI: 10.1080/21505594.2020.1809961] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The global incidence of Mycobacterium abscessus (Mabc), a rapidly growing nontuberculous mycobacterial strain that causes treatment-refractory pulmonary diseases, is increasing. Despite this, the host factors that allow for protection against infection are largely unknown. In this study, we found that sirtuin 3 (SIRT3), a mitochondrial protein deacetylase, plays a critical role in host defense against Mabc infection. Mabc decreased SIRT3 and upregulated mitochondrial oxidative stress in macrophages. SIRT3 deficiency led to increased bacterial loads, histopathological, and mitochondrial damage, and pathological inflammation during Mabc infection. Administration of scavengers of mitochondrial reactive oxygen species significantly decreased the in vivo Mabc burden and excessive inflammation, and induced SIRT3 expression in infected lungs. Notably, SIRT3 agonist (resveratrol) significantly decreased Mabc growth and attenuated inflammation in mice and zebrafishes, indicating the key role for SIRT3 in metazoan host defense. Collectively, these data strongly suggest that SIRT3 is a host-directed therapeutic target against Mabc infection by controlling mitochondrial homeostasis.
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Affiliation(s)
- Young Jae Kim
- Department of Microbiology, Chungnam National University College of Medicine , Daejeon, Korea.,Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea
| | - Sang-Hee Lee
- Center for Research Equipment, Korea Basic Science Institute , Cheongju, Chungbuk, South Korea
| | - Sang Min Jeon
- Department of Microbiology, Chungnam National University College of Medicine , Daejeon, Korea.,Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea
| | - Prashanta Silwal
- Department of Microbiology, Chungnam National University College of Medicine , Daejeon, Korea.,Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea
| | - Ju-Young Seo
- Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea.,College of Pharmacy, Chungnam National University , Daejeon, Republic of Korea
| | - Bui Thi Bich Hanh
- Molecular Mechanisms of Antibiotics, Division of Life Science, Research Institute of Life Science, Gyeongsang National University , Jinju, Korea.,Division of Applied Life Science (Bk21plus Program), Gyeongsang National University , Jinju, Korea
| | - June-Woo Park
- Department of Environmental Toxicology and Chemistry, Korea Institute of Toxicology , Jinju, Korea.,Human and Environmental Toxicology Program, Korea University of Science and Technology (UST) , Daejeon, Korea
| | - Jake Whang
- Korea Mycobacterium Resource Center (KMRC) & Basic Research Section, The Korean Institute of Tuberculosis (KIT) 168-5 , Cheongju-si, Chungcheongbuk-do, Republic of Korea
| | - Min Joung Lee
- Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea.,Department of Biochemistry, Chungnam National University College of Medicine , Korea
| | - Jun Young Heo
- Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea.,Department of Biochemistry, Chungnam National University College of Medicine , Korea.,Department of Medical Science, Chungnam National University College of Medicine , Daejeon, Korea
| | - Soon Ha Kim
- MitoImmune Therapeutics, Inc ., Ganhnam-gu, Seoul, Korea
| | - Jin-Man Kim
- Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea.,Department of Pathology; Chungnam National University College of Medicine , Korea
| | - Gyu Yong Song
- Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea.,College of Pharmacy, Chungnam National University , Daejeon, Republic of Korea
| | - Jichan Jang
- Molecular Mechanisms of Antibiotics, Division of Life Science, Research Institute of Life Science, Gyeongsang National University , Jinju, Korea
| | - Eun-Kyeong Jo
- Department of Microbiology, Chungnam National University College of Medicine , Daejeon, Korea.,Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea.,Department of Medical Science, Chungnam National University College of Medicine , Daejeon, Korea
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To Trap a Pathogen: Neutrophil Extracellular Traps and Their Role in Mucosal Epithelial and Skin Diseases. Cells 2021; 10:cells10061469. [PMID: 34208037 PMCID: PMC8230648 DOI: 10.3390/cells10061469] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/28/2021] [Accepted: 06/03/2021] [Indexed: 12/18/2022] Open
Abstract
Neutrophils are the most abundant circulating innate immune cells and comprise the first immune defense line, as they are the most rapidly recruited cells at sites of infection or inflammation. Their main microbicidal mechanisms are degranulation, phagocytosis, cytokine secretion and the formation of extracellular traps. Neutrophil extracellular traps (NETs) are a microbicidal mechanism that involves neutrophil death. Since their discovery, in vitro and in vivo neutrophils have been challenged with a range of stimuli capable of inducing or inhibiting NET formation, with the objective to understand its function and regulation in health and disease. These networks composed of DNA and granular components are capable of immobilizing and killing pathogens. They comprise enzymes such as myeloperoxidase, elastase, cathepsin G, acid hydrolases and cationic peptides, all with antimicrobial and antifungal activity. Therefore, the excessive formation of NETs can also lead to tissue damage and promote local and systemic inflammation. Based on this concept, in this review, we focus on the role of NETs in different infectious and inflammatory diseases of the mucosal epithelia and skin.
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Tomioka H, Tatano Y, Shimizu T, Sano C. Immunoadjunctive Therapy against Bacterial Infections Using Herbal Medicines Based on Th17 Cell-mediated Protective Immunity. Curr Pharm Des 2021; 27:3949-3962. [PMID: 34102961 DOI: 10.2174/1381612827666210608143449] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 04/27/2021] [Indexed: 11/22/2022]
Abstract
One of the major health concerns in the world is the global increase in intractable bacterial infectious diseases due to the emergence of multi- and extensively drug-resistant bacterial pathogens as well as an increase in compromised hosts around the world. Particularly, in the case of mycobacteriosis, the high incidence of tuberculosis in developing countries, resurgence of tuberculosis in industrialized countries, and increase in the prevalence of Mycobacterium avium complex infections are important worldwide health concerns. However, the development of novel antimycobacterial drugs is currently making slow progress. Therefore, it is considered that devising improved administration protocols for clinical treatment against refractory mycobacteriosis using existing chemotherapeutics is more practical than awaiting the development of new antimycobacterial drugs. The regulation of host immune responses using immunoadjunctive agents may increase the efficacy of antimicrobial treatment against mycobacteriosis. The same situations also exist in cases of intractable infectious diseases due to common bacteria other than mycobacteria. The mild and long-term up-regulation of host immune reactions in hosts with intractable chronic bacterial infections, using herbal medicines and medicinal plants, may be beneficial for such immunoadjunctive therapy. This review describes the current status regarding basic and clinical studies on therapeutic regimens using herbal medicines, useful for the clinical treatment of patients with intractable bacterial infections. In particular, we focus on immunoadjunctive effects of herbal medicines on the establishment and manifestation of host antibacterial immunity related to the immunological roles of Th17 cell lineages.
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Affiliation(s)
- Haruaki Tomioka
- Department of Basic Medical Science for Nursing, Department of Contemporary Psychology, Yasuda Women's University, Hiroshima, Japan
| | - Yutaka Tatano
- Department of Pharmaceutical Sciences, International University of Health and Welfare, Fukuoka, Japan
| | - Toshiaki Shimizu
- Department of Nutrition Administration, Yasuda Women's University, Hiroshima,, Japan
| | - Chiaki Sano
- Department of Community Medicine Management, Shimane University School of Medicine, Izumo, Japan
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The Oral Delivery of Water-Soluble Phenol TS-13 Ameliorates Granuloma Formation in an In Vivo Model of Tuberculous Granulomatous Inflammation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6652775. [PMID: 34093961 PMCID: PMC8140857 DOI: 10.1155/2021/6652775] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 05/03/2021] [Indexed: 11/17/2022]
Abstract
The redox-sensitive signaling system Keap1/Nrf2/ARE is a premier protective mechanism against oxidative stress that plays a key role in the pathogenesis and development of various diseases, including tuberculous granulomatous inflammation. We have previously reported that novel water-soluble phenolic antioxidant TS-13 (sodium 3-(4'-methoxyphenyl)propyl thiosulfonate) induces Keap1/Nrf2/ARE and attenuates inflammation. The aim of this study is the examination of the effect of TS-13 on tuberculous granulomatous inflammation. BALB/c mice were administered TS-13 (100 mg kg-1 day-1) through their drinking water starting immediately after Bacillus Calmette-Guérin (BCG) intravenous injection. Histological changes, production of reactive oxygen species (ROS) (activity of free-radical oxidation processes), and mRNA expression of Nrf2-driven, NF-κB-, AP-1-, and autophagy-dependent signal pathway genes in the liver and peritoneal exudate were evaluated 30 days later. After the 30th day of infection, the activity of the Keap1/Nrf2/ARE system was decreased and its effector genes entailed increasing ROS production in the liver. Therapeutic intervention with TS-13 is aimed at activating the Keap1/Nrf2/ARE system that leads to an increase in Nrf2 and Nrf2-mediated gene expression and a decrease in NF-κB expression. Changes in these pathways resulted in a decline of ROS production and a decrease in the number and the size of granulomas. In total, the results indicate that the Keap1/Nrf2/ARE system can be an effective pharmacological target in host-adjunctive treatment of tuberculosis.
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The protected physiological state of intracellular Salmonella enterica persisters reduces host cell-imposed stress. Commun Biol 2021; 4:520. [PMID: 33947954 PMCID: PMC8096953 DOI: 10.1038/s42003-021-02049-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 03/26/2021] [Indexed: 12/31/2022] Open
Abstract
During infectious diseases, small subpopulations of bacterial pathogens enter a non-replicating (NR) state tolerant to antibiotics. After phagocytosis, intracellular Salmonella enterica serovar Typhimurium (STM) forms persisters able to subvert immune defenses of the host. Physiological state and sensing properties of persisters are difficult to analyze, thus poorly understood. Here we deploy fluorescent protein reporters to detect intracellular NR persister cells, and to monitor their stress response on single cell level. We determined metabolic properties of NR STM during infection and demonstrate that NR STM persisters sense their environment and respond to stressors. Since persisters showed a lower stress response compared to replicating (R) STM, which was not consequence of lower metabolic capacity, the persistent state of STM serves as protective niche. Up to 95% of NR STM were metabolically active at beginning of infection, very similar to metabolic capacity of R STM. Sensing and reacting to stress with constant metabolic activity supports STM to create a more permissive environment for recurrent infections. Stress sensing and response of persister may be targeted by new antimicrobial approaches. Schulte et al. show that non-replicating Salmonella enterica serovar Typhimurium persisters, which are tolerant to antibiotics, sense their environment and respond to stressors. This study suggests that stress sensing and response of persisters may be targeted as an antimicrobial strategy.
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Hayford FEA, Ozturk M, Dolman RC, Blaauw R, Nienaber A, Loots DT, Brombacher F, Smuts CM, Parihar SP, Malan L. Longer-Term Omega-3 LCPUFA More Effective Adjunct Therapy for Tuberculosis Than Ibuprofen in a C3HeB/FeJ Tuberculosis Mouse Model. Front Immunol 2021; 12:659943. [PMID: 33995381 PMCID: PMC8113969 DOI: 10.3389/fimmu.2021.659943] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 04/08/2021] [Indexed: 12/22/2022] Open
Abstract
Advancement in the understanding of inflammation regulation during tuberculosis (TB) treatment has led to novel therapeutic approaches being proposed. The use of immune mediators like anti-inflammatory and pro-resolving molecules for such, merits attention. Drug repurposing is a widely used strategy that seeks to identify new targets to treat or manage diseases. The widely explored nonsteroidal anti-inflammatory drug (NSAID) ibuprofen and a more recently explored pharmaconutrition therapy using omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs), have the potential to modulate the immune system and are thus considered potential repurposed drugs in this context. These approaches may be beneficial as supportive therapy to the already existing treatment regimen to improve clinical outcomes. Here, we applied adjunct ibuprofen and n-3 LCPUFA therapy, respectively, with standard anti-TB treatment, in a C3HeB/FeJ murine model of TB. Bacterial loads, lung pathology, lung cytokines/chemokines and lung lipid mediators were measured as outcomes. Lung bacterial load on day 14 post-treatment (PT) was lower in the n-3 LCPUFA, compared to the ibuprofen group (p = 0.039), but was higher in the ibuprofen group than the treated control group (p = 0.0315). Treated control and ibuprofen groups had more free alveolar space initially as compared to the n-3 LCPUFA group (4 days PT, p= 0.0114 and p= 0.002, respectively); however, significantly more alveolar space was present in the n-3 LCPUFA group as compared to the ibuprofen group by end of treatment (14 days PT, p = 0.035). Interleukin 6 (IL-6) was lower in the ibuprofen group as compared to the treated control, EPA/DHA and untreated control groups at 4 days PT (p = 0.019, p = 0.019 and p = 0.002, respectively). Importantly, pro-resolving EPA derived 9-HEPE, 11-HEPE, 12-HEPE and 18-HEPE lipid mediators (LMs) were significantly higher in the EPA/DHA group as compared to the ibuprofen and treated control groups. This suggests that n-3 LCPUFAs do improve pro-resolving and anti-inflammatory properties in TB, and it may be safe and effective to co-administer as adjunct therapy with standard TB treatment, particularly longer-term. Also, our results show host benefits upon short-term co-administration of ibuprofen, but not throughout the entire TB treatment course.
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Affiliation(s)
- Frank E. A. Hayford
- Centre of Excellence for Nutrition, North-West University, Potchefstroom, South Africa
- Department of Dietetics, School of Biomedical and Allied Health Sciences, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Mumin Ozturk
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town-Component, University of Cape Town, Cape Town, South Africa
- Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, University of Cape Town, Cape Town, South Africa
| | - Robin C. Dolman
- Centre of Excellence for Nutrition, North-West University, Potchefstroom, South Africa
| | - Renee Blaauw
- Division of Human Nutrition, Stellenbosch University, Tygerberg, Cape Town, South Africa
| | - Arista Nienaber
- Centre of Excellence for Nutrition, North-West University, Potchefstroom, South Africa
| | - Du Toit Loots
- Laboratory of Infectious Disease Metabolomics, Human Metabolomics, North-West University, Potchefstroom, South Africa
| | - Frank Brombacher
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town-Component, University of Cape Town, Cape Town, South Africa
- Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, University of Cape Town, Cape Town, South Africa
- Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) and Institute of Infectious Diseases and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
| | - Cornelius M. Smuts
- Centre of Excellence for Nutrition, North-West University, Potchefstroom, South Africa
| | - Suraj P. Parihar
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town-Component, University of Cape Town, Cape Town, South Africa
- Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, University of Cape Town, Cape Town, South Africa
- Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) and Institute of Infectious Diseases and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
- Division of Medical Microbiology, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Linda Malan
- Centre of Excellence for Nutrition, North-West University, Potchefstroom, South Africa
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Kiran D, Basaraba RJ. Lactate Metabolism and Signaling in Tuberculosis and Cancer: A Comparative Review. Front Cell Infect Microbiol 2021; 11:624607. [PMID: 33718271 PMCID: PMC7952876 DOI: 10.3389/fcimb.2021.624607] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 01/13/2021] [Indexed: 12/16/2022] Open
Abstract
Infection with Mycobacterium tuberculosis (Mtb) leading to tuberculosis (TB) disease continues to be a major global health challenge. Critical barriers, including but not limited to the development of multi-drug resistance, lack of diagnostic assays that detect patients with latent TB, an effective vaccine that prevents Mtb infection, and infectious and non-infectious comorbidities that complicate active TB, continue to hinder progress toward a TB cure. To complement the ongoing development of new antimicrobial drugs, investigators in the field are exploring the value of host-directed therapies (HDTs). This therapeutic strategy targets the host, rather than Mtb, and is intended to augment host responses to infection such that the host is better equipped to prevent or clear infection and resolve chronic inflammation. Metabolic pathways of immune cells have been identified as promising HDT targets as more metabolites and metabolic pathways have shown to play a role in TB pathogenesis and disease progression. Specifically, this review highlights the potential role of lactate as both an immunomodulatory metabolite and a potentially important signaling molecule during the host response to Mtb infection. While long thought to be an inert end product of primarily glucose metabolism, the cancer research field has discovered the importance of lactate in carcinogenesis and resistance to chemotherapeutic drug treatment. Herein, we discuss similarities between the TB granuloma and tumor microenvironments in the context of lactate metabolism and identify key metabolic and signaling pathways that have been shown to play a role in tumor progression but have yet to be explored within the context of TB. Ultimately, lactate metabolism and signaling could be viable HDT targets for TB; however, critical additional research is needed to better understand the role of lactate at the host-pathogen interface during Mtb infection before adopting this HDT strategy.
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Affiliation(s)
| | - Randall J. Basaraba
- Metabolism of Infectious Diseases Laboratory, Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States
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Zhang S, Li G, Bi J, Guo Q, Fu X, Wang W, Liu S, Xiao G, Ou M, Zhang J, He X, Li F, Li G, Feng CG, Chen X, Zhang G. Functional nucleotide polymorphisms up-regulating transforming growth factor β1 expression are associated with increased tuberculosis susceptibility. J Infect Dis 2020; 225:825-835. [PMID: 32939551 PMCID: PMC8889291 DOI: 10.1093/infdis/jiaa585] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 09/14/2020] [Indexed: 12/13/2022] Open
Abstract
Previous studies demonstrated that transforming growth factor (TGT) β1 plays an immunosuppressive role in clinical tuberculosis. However, the contribution of TGF-β1 gene polymorphisms to human tuberculosis susceptibility remains undetermined. In this study, we showed that single-nucleotide polymorphisms (SNPs) in TGF-β1 gene were associated with increased susceptibility to tuberculosis in the discovery cohort (1533 case patients and 1445 controls) and the validation cohort (832 case patients and 1084 controls), and 2 SNPs located in the promoter region (rs2317130 and rs4803457) are in strong linkage disequilibrium. The SNP rs2317130 was associated with the severity of tuberculosis. Further investigation demonstrated that rs2317130 CC genotype is associated with higher TGF-β1 and interleukin 17A production. The mechanistic study showed that rs2317130 C allele affected TGF-β1 promoter activity by regulating binding activity to nuclear extracts. These findings provide insights into the pathogenic role of TGF-β1 in human tuberculosis and reveal a function for the TGF-β1 promoter SNPs in regulating immune responses during Mycobacterium tuberculosis infection.
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Affiliation(s)
- Su Zhang
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China.,Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, China
| | - Guobao Li
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Jing Bi
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Qinglong Guo
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Xiangdong Fu
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Wenfei Wang
- Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, China
| | - Shuyan Liu
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Guohui Xiao
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Min Ou
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Juanjuan Zhang
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Xing He
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Fang Li
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Guanqiang Li
- Department of Laboratory Medicine, Shenzhen Longgang People's Hospital, The Chinese University of Hong Kong, Shenzhen, China
| | - Carl G Feng
- Department of Infectious Diseases and Immunology, Sydney Medical School, the University of Sydney, Sydney, NSW, Australia
| | - Xinchun Chen
- Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, China
| | - Guoliang Zhang
- National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China.,Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, China
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42
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Lapenkova MB, Alyapkina YS, Vladimirsky MA. Bactericidal Activity of Liposomal Form of Lytic Mycobacteriophage D29 in Cell Models of Tuberculosis Infection In Vitro. Bull Exp Biol Med 2020; 169:361-364. [PMID: 32743783 DOI: 10.1007/s10517-020-04887-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Indexed: 11/28/2022]
Abstract
The use of lytic mycobacteriophages to treat tuberculosis under conditions of acquired resistance to anti-tuberculosis drugs is one of the most practical ways to improve the effectiveness of therapy and reduce the spread of this disease. We studied the efficacy of antimycobacterial action of mycobacteriophage D29 encapsulated into 400-nm liposomes in cell models of tuberculosis infection in vitro. The antimycobacterial action of lytic mycobacteriophage D29 used in free or liposome-encapsulated forms was demonstrated on cell models of intracellularly infected RAW264.7 macrophages and tuberculous granuloma formed by human blood mononuclear cells. The experiments demonstrated pronounced advantage of liposomal form of mycobacteriophage according to the criteria of their penetration into macrophages and lysis of Mycobacterium tuberculosis in culture.
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Affiliation(s)
- M B Lapenkova
- National Medical Research Center for Phthisiopulmonology and Infectious Diseases, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Yu S Alyapkina
- National Medical Research Center for Phthisiopulmonology and Infectious Diseases, Ministry of Health of the Russian Federation, Moscow, Russia
| | - M A Vladimirsky
- National Medical Research Center for Phthisiopulmonology and Infectious Diseases, Ministry of Health of the Russian Federation, Moscow, Russia.
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43
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Hasby Saad MA, El-Anwar N. Bevacizumab as a potential anti-angiogenic therapy in schistosomiasis: A double-edged, but adjustable weapon. Parasite Immunol 2020; 42:e12724. [PMID: 32338371 DOI: 10.1111/pim.12724] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 04/09/2020] [Accepted: 04/17/2020] [Indexed: 11/30/2022]
Abstract
AIM Investigating the anti-angiogenic effect of bevacizumab on chronic schistosomiasis mansoni in a trial to hinder the Schistosome-induced angiogenesis and porto-systemic shunting complications. METHODS The immunohistochemical expression of CD34, VEGF-R1, PCNA and α-SMA (angiogenesis markers) was analysed in the lung, liver and gastrointestinal junctions of chronic S mansoni infected mice after intraperitoneal injection of bevacizumab. The effect of prolonged administration of bevacizumab with praziquantel was also assessed through parasitic load, protective index, granuloma and fibrous tissue evaluation. RESULTS A regression in the vascular activity and microvascular density was observed in the infected mice after receiving bevacizumab. They had a significantly less VEGF-R1, PCNA, CD-34 and α-SMA expression in comparison to the infected untreated mice. The least tissue egg count was reported in mice received bevacizumab for 6 weeks (Mean = 27 120). However, they had persistent liver granulomas, and massively amalgamated fibrosis. Interestingly, the least faecal egg and tissue worms counts (Mean = 112, 13.4), and the highest protection index (39.26) were reported in mice received bevacizumab for 3 weeks, with marked granuloma, and fibrous tissue resolution. CONCLUSIONS Bevacizumab has a promising protective effect against the Schistosoma-induced angiogenesis. As an adjuvant to praziquantel, it is important to adjust the appropriate duration of administration that achieves the best schistosomicidal effect without impeding granuloma and fibrous tissue resolution.
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Affiliation(s)
- Marwa A Hasby Saad
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Gharbia Governorate, Egypt
| | - Noha El-Anwar
- Department of Pathology, Tanta University, Faculty of Medicine, Tanta, Egypt
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44
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Muefong CN, Sutherland JS. Neutrophils in Tuberculosis-Associated Inflammation and Lung Pathology. Front Immunol 2020; 11:962. [PMID: 32536917 PMCID: PMC7266980 DOI: 10.3389/fimmu.2020.00962] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 04/23/2020] [Indexed: 12/13/2022] Open
Abstract
Protective immunity to Mycobacterium tuberculosis (Mtb)—the causative agent of tuberculosis (TB)—is not fully understood but involves immune responses within the pulmonary airways which can lead to exacerbated inflammation and immune pathology. In humans, this inflammation results in lung damage; the extent of which depends on specific host pro-inflammatory processes. Neutrophils, though increasingly linked to the development of inflammatory disorders, have been less well studied in relation to TB-induced lung pathology. Neutrophils mode of action and their specialized functions can be directly linked to TB-specific lung tissue damage observed on patient chest X-rays at diagnosis and contribute to long-term pulmonary sequelae. This review discusses aspects of neutrophil activity associated with active TB, including the resulting inflammation and pulmonary impairment. It highlights the significance of neutrophil function on TB disease outcome and underlines the necessity of monitoring neutrophil function for better assessment of the immune response and severity of lung pathology associated with TB. Finally, we propose that some MMPs, ROS, MPO, S100A8/A9 and Glutathione are neutrophil-related inflammatory mediators with promising potential as targets for developing host-directed therapies for TB.
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Affiliation(s)
- Caleb N Muefong
- Vaccines and Immunity Theme, Medical Research Council Unit, The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, The Gambia
| | - Jayne S Sutherland
- Vaccines and Immunity Theme, Medical Research Council Unit, The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, The Gambia
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Krishnamoorthy G, Kaiser P, Abu Abed U, Weiner J, Moura-Alves P, Brinkmann V, Kaufmann SHE. FX11 limits Mycobacterium tuberculosis growth and potentiates bactericidal activity of isoniazid through host-directed activity. Dis Model Mech 2020; 13:dmm041954. [PMID: 32034005 PMCID: PMC7132771 DOI: 10.1242/dmm.041954] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 01/23/2020] [Indexed: 12/14/2022] Open
Abstract
Lactate dehydrogenase A (LDHA) mediates interconversion of pyruvate and lactate, and increased lactate turnover is exhibited by malignant and infected immune cells. Hypoxic lung granuloma in Mycobacterium tuberculosis-infected animals present elevated levels of Ldha and lactate. Such alterations in the metabolic milieu could influence the outcome of host-M. tuberculosis interactions. Given the central role of LDHA for tumorigenicity, targeting lactate metabolism is a promising approach for cancer therapy. Here, we sought to determine the importance of LDHA for tuberculosis (TB) disease progression and its potential as a target for host-directed therapy. To this end, we orally administered FX11, a known small-molecule NADH-competitive LDHA inhibitor, to M. tuberculosis-infected C57BL/6J mice and Nos2-/- mice with hypoxic necrotizing lung TB lesions. FX11 did not inhibit M. tuberculosis growth in aerobic/hypoxic liquid culture, but modestly reduced the pulmonary bacterial burden in C57BL/6J mice. Intriguingly, FX11 administration limited M. tuberculosis replication and onset of necrotic lung lesions in Nos2-/- mice. In this model, isoniazid (INH) monotherapy has been known to exhibit biphasic killing kinetics owing to the probable selection of an INH-tolerant bacterial subpopulation. However, adjunct FX11 treatment corrected this adverse effect and resulted in sustained bactericidal activity of INH against M. tuberculosis As a limitation, LDHA inhibition as an underlying cause of FX11-mediated effect could not be established as the on-target effect of FX11 in vivo was unconfirmed. Nevertheless, this proof-of-concept study encourages further investigation on the underlying mechanisms of LDHA inhibition and its significance in TB pathogenesis.
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Affiliation(s)
| | - Peggy Kaiser
- Department of Immunology, Max Planck Institute for Infection Biology, Berlin 10117, Germany
| | - Ulrike Abu Abed
- Core Facility Microscopy, Max Planck Institute for Infection Biology, Berlin 10117, Germany
| | - January Weiner
- Department of Immunology, Max Planck Institute for Infection Biology, Berlin 10117, Germany
| | - Pedro Moura-Alves
- Department of Immunology, Max Planck Institute for Infection Biology, Berlin 10117, Germany
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK
| | - Volker Brinkmann
- Core Facility Microscopy, Max Planck Institute for Infection Biology, Berlin 10117, Germany
| | - Stefan H E Kaufmann
- Department of Immunology, Max Planck Institute for Infection Biology, Berlin 10117, Germany
- Hagler Institute for Advanced Study at Texas A&M University, College Station, TX 77843-3572, USA
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Tsenova L, Singhal A. Effects of host-directed therapies on the pathology of tuberculosis. J Pathol 2020; 250:636-646. [PMID: 32108337 DOI: 10.1002/path.5407] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 02/12/2020] [Accepted: 02/24/2020] [Indexed: 12/15/2022]
Abstract
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has co-evolved with the human immune system and utilizes multiple strategies to persist within infected cells, to hijack several immune mechanisms, and to cause severe pathology and tissue damage in the host. This delays the efficacy of current antibiotic therapy and contributes to the evolution of multi-drug-resistant strains. These challenges led to the development of the novel approach in TB treatment that involves therapeutic targeting of host immune response to control disease pathogenesis and pathogen growth, namely, host-directed therapies (HDTs). Such HDT approaches can (1) enhance the effect of antibiotics, (2) shorten treatment duration for any clinical form of TB, (3) promote development of immunological memory that could protect against relapse, and (4) ameliorate the immunopathology including matrix destruction and fibrosis associated with TB. In this review we discuss TB-HDT candidates shown to be of clinical relevance that thus could be developed to reduce pathology, tissue damage, and subsequent impairment of pulmonary function. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Liana Tsenova
- Department of Biological Sciences, New York City College of Technology, Brooklyn, NY, USA
| | - Amit Singhal
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.,Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.,Vaccine and Infectious Disease Research Centre (VIDRC), Translational Health Science and Technology Institute (THSTI), Faridabad, India
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Multi-functionalized nanocarriers targeting bacterial reservoirs to overcome challenges of multi drug-resistance. ACTA ACUST UNITED AC 2020; 28:319-332. [PMID: 32193748 DOI: 10.1007/s40199-020-00337-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 03/11/2020] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Infectious diseases associated with intracellular bacteria such as Staphylococcus aureus, Salmonella typhimurium and Mycobacterium tuberculosis are important public health concern. Emergence of multi and extensively drug-resistant bacterial strains have made it even more obstinate to offset such infections. Bacteria residing within intracellular compartments provide additional barriers to effective treatment. METHOD Information provided in this review has been collected by accessing various electronic databases including Google scholar, Web of science, Scopus, and Nature index. Search was performed using keywords nanoparticles, intracellular targeting, multidrug resistance, Staphylococcus aureus; Salmonella typhimurium; Mycobacterium tuberculosis. Information gathered was categorized into three major sections as 'Intracellular targeting of Staphylococcus aureus, Intracellular targeting of Salmonella typhimurium and Intracellular targeting of Mycobacterium tuberculosis' using variety of nanocarrier systems. RESULTS Conventional management for infectious diseases typically comprises of long-term treatment with a combination of antibiotics, which may lead to side effects and decreased patient compliance. A wide range of multi-functionalized nanocarrier systems have been studied for delivery of drugs within cellular compartments where bacteria including Staphylococcus aureus, Salmonella typhimurium and Mycobacterium tuberculosis reside. Such carrier systems along with targeted delivery have been utilized for sustained and controlled delivery of drugs. These strategies have been found useful in overcoming the drawbacks of conventional treatments including multi-drug resistance. CONCLUSION Development of multi-functional nanocargoes encapsulating antibiotics that are proficient in targeting and releasing drug into infected reservoirs seems to be a promising strategy to circumvent the challenge of multidrug resistance. Graphical abstract.
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Minakshi P, Ghosh M, Brar B, Kumar R, Lambe UP, Ranjan K, Manoj J, Prasad G. Nano-antimicrobials: A New Paradigm for Combating Mycobacterial Resistance. Curr Pharm Des 2020; 25:1554-1579. [PMID: 31218956 DOI: 10.2174/1381612825666190620094041] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 06/11/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Mycobacterium group contains several pathogenic bacteria including M. tuberculosis where the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) is alarming for human and animal health around the world. The condition has further aggravated due to the speed of discovery of the newer drugs has been outpaced by the rate of resistance developed in microorganisms, thus requiring alternative combat strategies. For this purpose, nano-antimicrobials have emerged as a potential option. OBJECTIVE The current review is focused on providing a detailed account of nanocarriers like liposome, micelles, dendrimers, solid lipid NPs, niosomes, polymeric nanoparticles, nano-suspensions, nano-emulsion, mesoporous silica and alginate-based drug delivery systems along with the recent updates on developments regarding nanoparticle-based therapeutics, vaccines and diagnostic methods developed or under pipeline with their potential benefits and limitations to combat mycobacterial diseases for their successful eradication from the world in future. RESULTS Distinct morphology and the underlying mechanism of pathogenesis and resistance development in this group of organisms urge improved and novel methods for the early and efficient diagnosis, treatment and vaccination to eradicate the disease. Recent developments in nanotechnology have the potential to meet both the aspects: nano-materials are proven components of several efficient targeted drug delivery systems and the typical physicochemical properties of several nano-formulations have shown to possess distinct bacteriocidal properties. Along with the therapeutic aspects, nano-vaccines and theranostic applications of nano-formulations have grown in popularity in recent times as an effective alternative means to combat different microbial superbugs. CONCLUSION Nanomedicine holds a bright prospect to perform a key role in global tuberculosis elimination program.
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Affiliation(s)
- Prasad Minakshi
- Department of Animal Biotechnology, LLR University of Veterinary and Animal Sciences, Hisar-125 004, Haryana, India
| | - Mayukh Ghosh
- Department of Veterinary Biochemistry, Ranchi Veterinary College, Birsa Agricultural University, Ranchi-834 006, Jharkhand, India
| | - Basanti Brar
- Department of Animal Biotechnology, LLR University of Veterinary and Animal Sciences, Hisar-125 004, Haryana, India
| | - Rajesh Kumar
- Department of Veterinary Physiology, COVAS, KVASU, Pookode, Wayanad- 673576, Kerala, India
| | - Upendra P Lambe
- Department of Animal Biotechnology, LLR University of Veterinary and Animal Sciences, Hisar-125 004, Haryana, India
| | | | - Jinu Manoj
- RVDEC Mahendergarh, LUVAS, Haryana, India
| | - Gaya Prasad
- SVP University of Agriculture and Technology, Meerut, India
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Fenofibrate Facilitates Post-Active Tuberculosis Infection in Macrophages and is Associated with Higher Mortality in Patients under Long-Term Treatment. J Clin Med 2020; 9:jcm9020337. [PMID: 31991736 PMCID: PMC7073736 DOI: 10.3390/jcm9020337] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 01/19/2020] [Accepted: 01/21/2020] [Indexed: 02/05/2023] Open
Abstract
Background: Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that infects and persists in macrophages. This study aimed to investigate the effects of long-term fenofibrate treatment in patients with tuberculosis (TB), and the intracellular viability of Mtb in human macrophages. Methods: Epidemiological data from the National Health Insurance Research Database of Taiwan were used to present outcomes of TB patients treated with fenofibrate. In the laboratory, we assessed Mtb infection in macrophages treated with or without fenofibrate. Mtb growth, lipid accumulation in macrophages, and expression of transcriptional genes were examined. Results: During 11 years of follow-up, TB patients treated with fenofibrate presented a higher risk of mortality. Longer duration of fenofibrate use was associated with a significantly higher risk of mortality. Treatment with fenofibrate significantly increased the number of bacilli in human macrophages in vitro. Fenofibrate did not reduce, but induced an increasing trend in the intracellular lipid content of macrophages. In addition, dormant genes of Mtb, icl1, tgs1, and devR, were markedly upregulated in response to fenofibrate treatment. Our results suggest that fenofibrate may facilitate intracellular Mtb persistence. Conclusions: Our data shows that long-term treatment with fenofibrate in TB patients is associated with a higher mortality. The underlying mechanisms may partly be explained by the upregulation of Mtb genes involved in lipid metabolism, enhanced intracellular growth of Mtb, and the ability of Mtb to sustain a nutrient-rich reservoir in human macrophages, observed during treatment with fenofibrate.
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Kan Y, Meng L, Xie L, Liu L, Dong W, Feng J, Yan Y, Zhao C, Peng G, Wang D, Lu M, Yang C, Niu C. Temporal modulation of host aerobic glycolysis determines the outcome of Mycobacterium marinum infection. FISH & SHELLFISH IMMUNOLOGY 2020; 96:78-85. [PMID: 31775059 DOI: 10.1016/j.fsi.2019.11.051] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 11/19/2019] [Accepted: 11/22/2019] [Indexed: 06/10/2023]
Abstract
Macrophages are the first-line host defense that the invading Mycobacterium tuberculosis (Mtb) encounters. It has been recently reported that host aerobic glycolysis was elevated post the infection by a couple of virulent mycobacterial species. However, whether this metabolic transition is required for host defense against intracellular pathogens and the underlying mechanisms remain to be further investigated. A pathogenic mycobacterial species, M. marinum, is genetically close to Mtb and was utilized in this study. Through analyzing cellular carbon metabolism of RAW 264.7 (a murine macrophage-like cell line) post M. marinum infection, a strong elevation of glycolysis was observed. Next, three glycolysis inhibitors were examined for their ability to inhibit mycobacterial proliferation inside RAW264.7 macrophages. Among them, a glucose analog, 2-deoxyglucose (2-DG) displayed a protective role against mycobacterial infection. Treatment with 2-DG at concentrations of 0.5 or 1 mM significantly induced autophagy and decreased the phagocytosis of M. marinum by macrophages. Moreover, 2-DG pre-treatment exerted a significantly protective effect on zebrafish larvae by limiting the proliferation of M. marinum, and such effect was correlated to tumor necrosis factor alpha (TNF-α) as the 2-DG pre-treatment increased the expression of TNF-α in both mouse peritoneal macrophages and zebrafish. On the contrary, the 2-DG treatment post infection did not restrain proliferation of M. marinum in WT zebrafish, and even accelerated bacterial replication in TNF-α-/- zebrafish. Together, modulation of glycolysis prior to infection boosts host immunity against M. marinum infection, indicating a potential intervention strategy to control mycobacterial infection.
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Affiliation(s)
- Yuanqing Kan
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lu Meng
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China; CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, China
| | - Lingling Xie
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lixia Liu
- Shanghai Institute of Plant Physiology and Ecology, Shanghai Institutes of Biologic Sciences (SIBS), Chinese Academy of Sciences, Shanghai, China
| | - Wenyue Dong
- Shanghai Institute of Plant Physiology and Ecology, Shanghai Institutes of Biologic Sciences (SIBS), Chinese Academy of Sciences, Shanghai, China
| | - Jintao Feng
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yuchen Yan
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chao Zhao
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Gang Peng
- Institute of Brain Sciences, Fudan University, Shanghai, China
| | - Decheng Wang
- Medical College, China Three Gorges University, Yichang, 443002, China
| | - Mingfang Lu
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chen Yang
- Shanghai Institute of Plant Physiology and Ecology, Shanghai Institutes of Biologic Sciences (SIBS), Chinese Academy of Sciences, Shanghai, China
| | - Chen Niu
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
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