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Haindongo NJ, Seheri M, Magwira CA. Significant abundance of bacterial flagellin and expression of its surface localized receptor toll-like receptor 5 and cytokine interleukin-22 in South African infants with poor oral rotavirus vaccine take. Gut Pathog 2025; 17:3. [PMID: 39825457 PMCID: PMC11740523 DOI: 10.1186/s13099-024-00672-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 10/20/2024] [Accepted: 12/24/2024] [Indexed: 01/20/2025] Open
Abstract
Bacterial flagellin, a potent intestinal innate immune activator, prevents murine rotavirus (RV) infection independent of adaptive immunity and interferons. The flagellin-induced immunity is mediated by Toll-like receptor (TLR5) and Nod-like receptor C4 (NLRC4), which elicit the production of interleukins 22 (IL-22) and IL-18, respectively. Here, we assessed whether a high abundance of flagellin at the time of vaccination would negatively affect the oral RV vaccine take. Fecal samples were collected from infants a week after first dose of Rotarix vaccination to establish vaccine shedders (n = 50) and non-shedders (n = 44). The abundance of flagellin and expression of flagellin-encoding fliC, TLR5 and NLRC4, IL-22 and IL-18 genes was determined by qPCR. There were no differences in the abundance of flagellin between vaccine shedders and non-shedders (p = 0.15). However, the expression of FliC was increased 7.5-fold in non-shedders versus shedders (p = 0.001). Similarly, TLR5 (p = 0.045), and not NLRC4 (p = 0.507,) was significantly expressed in non-shedders versus shedders. The expression of IL-22 (p = 0.054), and not IL-18 dependent NLRC4 (p = 0.650), was increased 3.4-fold in non-shedders versus shedders. Collectively, our observations suggest a possible negative impact of the abundance of viable flagellated bacteria at the time of vaccination on the replication and therefore the performance of RV vaccines.
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Affiliation(s)
- Nontlantla J Haindongo
- Diarrheal Pathogens Research Unit (DPRU), Department of Virology, Sefako Makgatho Health Sciences University, Ga-rankuwa, Pretoria, South Africa
| | - Mapaseka Seheri
- Diarrheal Pathogens Research Unit (DPRU), Department of Virology, Sefako Makgatho Health Sciences University, Ga-rankuwa, Pretoria, South Africa
| | - Cliff A Magwira
- Diarrheal Pathogens Research Unit (DPRU), Department of Virology, Sefako Makgatho Health Sciences University, Ga-rankuwa, Pretoria, South Africa.
- Department of Medical Virology, School of Medicine, Sefako Makgatho Health Sciences University, Molotlegi St, Ga-Rankuwa 0208, Pretoria, South Africa.
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Li L, Ji L, Chen J, Hou S, Yang Y, Wang W, Lei B, Zhang W, Zhao K, Zhao Z, Yuan W. Host-derived Bacillus antagonistic novel duck reovirus infection by regulating gut microbiota-mediated immune responses. Vet Microbiol 2025; 300:110332. [PMID: 39647218 DOI: 10.1016/j.vetmic.2024.110332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/18/2024] [Revised: 11/25/2024] [Accepted: 12/03/2024] [Indexed: 12/10/2024]
Abstract
The Novel Duck Reovirus (NDRV) infection poses a significant health risk to ducks, primarily attributed to the absence of efficacious preventive measures. This research aimed to investigate whether the administration of isolated Bacillus could protect antagonistic NDRV infection in a Cherry Valley duck model. Four indigenous Bacillus strains from the feces of healthy ducks demonstrated promising biosafety profiles. One-day-old ducklings were inoculated intramuscularly with NDRV and subsequently subjected to a 28-day regimen of mixed Bacillus (Bac) treatment. The effects of Bac on pathological symptoms, immune response and intestinal flora were analyzed. The results showed that Bac significantly reduced weight loss, clinical symptoms, and viral loading. Moreover, Bac treatment significantly decreased neutrophils, monocytes proportion, the TNF-α, IL-1β and IL-6 expression, increased platelets, lymphocytes proportion, the IFN-β and IL-10 expression, and restored immune dysfunction. In addition, Bac has increased the relative abundance of Enterococcaceae, Lactobacillales, Bacilli, Ruminococcaceae, Clostridium and Phascolarctobacterium. Moreover, the metabolism of short-chain fatty acids (SCFAs) was further regulated, thereby enhancing the acetate content. The correlation analysis showed that a positive association between acetate levels and IFN-β expression, while a negative correlation was observed with viral loading. In conclusion, the results suggest that the anti-NDRV mechanism of Bac may involve the modulation of gut microbiota to elicit an immune response that inhibits viral infection. This study presents a novel approach for the prevention and treatment of NDRV, thereby establishing a theoretical foundation for the future development of probiotics in the prevention and treatment of NDRV.
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Affiliation(s)
- Lijie Li
- College of Veterinary Medicine, Hebei Agricultural University, NO.2596 Lekai South Street, Baoding, Hebei 071000, China; Veterinary Biological Technology Innovation Centre of Hebei Province, Baoding, Hebei 071000, China
| | - Longhai Ji
- College of Veterinary Medicine, Hebei Agricultural University, NO.2596 Lekai South Street, Baoding, Hebei 071000, China; Veterinary Biological Technology Innovation Centre of Hebei Province, Baoding, Hebei 071000, China
| | - Jiawei Chen
- College of Veterinary Medicine, Hebei Agricultural University, NO.2596 Lekai South Street, Baoding, Hebei 071000, China; Veterinary Biological Technology Innovation Centre of Hebei Province, Baoding, Hebei 071000, China
| | - Suli Hou
- College of Veterinary Medicine, Hebei Agricultural University, NO.2596 Lekai South Street, Baoding, Hebei 071000, China; Veterinary Biological Technology Innovation Centre of Hebei Province, Baoding, Hebei 071000, China
| | - Yuchuan Yang
- College of Veterinary Medicine, Hebei Agricultural University, NO.2596 Lekai South Street, Baoding, Hebei 071000, China; Veterinary Biological Technology Innovation Centre of Hebei Province, Baoding, Hebei 071000, China
| | - Weizhu Wang
- College of Veterinary Medicine, Hebei Agricultural University, NO.2596 Lekai South Street, Baoding, Hebei 071000, China; Veterinary Biological Technology Innovation Centre of Hebei Province, Baoding, Hebei 071000, China
| | - Baishi Lei
- College of Veterinary Medicine, Hebei Agricultural University, NO.2596 Lekai South Street, Baoding, Hebei 071000, China; Veterinary Biological Technology Innovation Centre of Hebei Province, Baoding, Hebei 071000, China
| | - Wuchao Zhang
- College of Veterinary Medicine, Hebei Agricultural University, NO.2596 Lekai South Street, Baoding, Hebei 071000, China; Veterinary Biological Technology Innovation Centre of Hebei Province, Baoding, Hebei 071000, China
| | - Kuan Zhao
- College of Veterinary Medicine, Hebei Agricultural University, NO.2596 Lekai South Street, Baoding, Hebei 071000, China; Veterinary Biological Technology Innovation Centre of Hebei Province, Baoding, Hebei 071000, China
| | - Zhuo Zhao
- Beijing Centrebio Biological Co., Ltd, Beijing 102629, China.
| | - Wanzhe Yuan
- College of Veterinary Medicine, Hebei Agricultural University, NO.2596 Lekai South Street, Baoding, Hebei 071000, China; Veterinary Biological Technology Innovation Centre of Hebei Province, Baoding, Hebei 071000, China.
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3
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Kumar V, Stewart Iv JH. Platelet's plea to Immunologists: Please do not forget me. Int Immunopharmacol 2024; 143:113599. [PMID: 39547015 DOI: 10.1016/j.intimp.2024.113599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/09/2024] [Revised: 10/07/2024] [Accepted: 11/06/2024] [Indexed: 11/17/2024]
Abstract
Platelets are non-nucleated mammalian cells originating from the cytoplasmic expulsion of the megakaryocytes. Megakaryocytes develop during hematopoiesis through megakaryopoiesis, whereas platelets develop from megakaryocytes through thrombopoiesis. Since their first discovery, platelets have been studied as critical cells controlling hemostasis or blood coagulation. However, coagulation and innate immune response are evolutionarily linked processes. Therefore, it has become critical to investigate the immunological functions of platelets to maintain immune homeostasis. Advances in immunology and platelet biology research have explored different critical roles of platelets, including phagocytosis, release of different immune mediators, and controlling functions of different immune cells by direct interaction and immune mediators. The current article discusses platelet's development and their critical role as innate immune cells, which express different pattern recognition receptors (PRRs), recognizing different pathogen or microbe-associated molecular patterns (PAMPs or MAMPs) and death/damage-associated molecular patterns (DAMPs) and their direct interactions with innate and adaptive immune cells to maintain immune homeostasis.
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Affiliation(s)
- Vijay Kumar
- Department of Surgery, Laboratory of Tumor Immunology and Immunotherapy, Medical Education Building-C, Morehouse School of Medicine, 720 Westview Drive, Atlanta, GA 30310 USA.
| | - John H Stewart Iv
- Department of Surgery, Laboratory of Tumor Immunology and Immunotherapy, Medical Education Building-C, Morehouse School of Medicine, 720 Westview Drive, Atlanta, GA 30310 USA
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Collins C, Chaumont L, Peruzzi M, Jamak N, Boudinot P, Béjar J, Moreno P, Álvarez Torres D, Collet B. Effect of a loss of the mda5/ifih1 gene on the antiviral resistance in a Chinook salmon Oncorhynchus tshawytscha cell line. PLoS One 2024; 19:e0311283. [PMID: 39401233 PMCID: PMC11472919 DOI: 10.1371/journal.pone.0311283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/23/2024] [Accepted: 09/17/2024] [Indexed: 10/17/2024] Open
Abstract
Cells are equipped with intracellular RIG-like Receptors (RLRs) detecting double stranded (ds)RNA, a molecule with Pathogen-Associated Molecular Pattern (PAMPs) generated during the life cycle of many viruses. Melanoma Differentiation-Associated protein 5 (MDA5), a helicase enzyme member of the RLRs encoded by the ifih1 gene, binds to long dsRNA molecules during a viral infection and initiates production of type I interferon (IFN1) which orchestrates the antiviral response. In order to understand the contribution of MDA5 to viral resistance in fish cells, we have isolated a clonal Chinook salmon Oncorhynchus tshawytscha epithelial-like cell line invalidated for the ifih1 gene by CRISPR/Cas9 genome editing. We demonstrated that IFN1 induction is impaired in this cell line after infection with the Snakehead Rhabdovirus (SHRV), the Salmon Alphavirus (SAV) or Nervous Necrosis Virus (NNV). The cell line, however, did not show any increase in cytopathic effect when infected with SHRV or SAV. Similarly, no cytopathic effect was observed in the ifih1-/- cell line when infected with Infectious Pancreatic Necrosis Virus (IPNV), Infectious Haemorrhagic Necrotic Virus (IHNV). These results indicate the redundancy of the antiviral innate defence system in CHSE-derived cells, which helps with circumventing viral evasion strategies.
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Affiliation(s)
- Catherine Collins
- INRAE, UVSQ, VIM, Université Paris-Saclay, Jouy-en-Josas, France
- School of Biological, Earth and Environmental Sciences, University College Cork, Cork, Ireland
| | - Lise Chaumont
- INRAE, UVSQ, VIM, Université Paris-Saclay, Jouy-en-Josas, France
| | - Mathilde Peruzzi
- INRAE, UVSQ, VIM, Université Paris-Saclay, Jouy-en-Josas, France
| | - Nedim Jamak
- INRAE, UVSQ, VIM, Université Paris-Saclay, Jouy-en-Josas, France
| | - Pierre Boudinot
- INRAE, UVSQ, VIM, Université Paris-Saclay, Jouy-en-Josas, France
| | | | | | | | - Bertrand Collet
- INRAE, UVSQ, VIM, Université Paris-Saclay, Jouy-en-Josas, France
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Zhang RR, Yang XY, Yang YL, Guo TK, Huang JS, Yang YS, Shi CW, Yang GL, Huang HB, Wang JZ, Jiang YL, Cao X, Wang N, Zeng Y, Yang WT, Wang CF. TLR3/TRIF and MAVS Signaling Is Essential in Regulating Mucosal T Cell Responses during Rotavirus Infection. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 213:1008-1022. [PMID: 39194407 DOI: 10.4049/jimmunol.2300867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 12/14/2023] [Accepted: 07/30/2024] [Indexed: 08/29/2024]
Abstract
The functions of the natural dsRNA sensors TLR3 (TRIF) and RIG-I (MAVS) are crucial during viral challenge and have not been accurately clarified in adaptive immune responses to rotavirus (RV) infection. In this study, we found that RV infection caused severe pathological damage to the small intestine of TLR3-/- and TRIF-/- mice. Our data found that dendritic cells from TLR3-/- and TRIF-/- mice had impaired Ag presentation to the RV and attenuated initiation of T cells upon viral infection. These attenuated functions resulted in impaired CD4+ T and CD8+ T function in mice lacking TLR3-TRIF signaling postinfection. Additionally, attenuated proliferative capacity of T cells from TLR3-/- and TRIF-/- mice was observed. Subsequently, we observed a significant reduction in the absolute number of memory T cells in the spleen and mesenteric lymph node (MLN) of TRIF-/- recipient mice following RV infection in a bone marrow chimeric model. Furthermore, there was reduced migration of type 2 classical dendritic cells from the intestine to MLNs after RV infection in TLR3-/- and TRIF-/- mice. Notably, RV infection resulted in attenuated killing of spleen and MLN tissues in TRIF-/- and MAVS-/- mice. Finally, we demonstrated that RV infection promoted apoptosis of CD8+ T cells in TRIF-/- and TLR3-/-MAVS-/- mice. Taken together, our findings highlight an important mechanism of TLR3 signaling through TRIF in mucosal T cell responses to RV and lay the foundation for the development of a novel vaccine.
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Affiliation(s)
- Rong-Rong Zhang
- College of Veterinary Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Xue-Yao Yang
- College of Veterinary Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Yong-Lei Yang
- College of Veterinary Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Tian-Kui Guo
- College of Veterinary Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Jing-Shu Huang
- College of Veterinary Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Ying-Shi Yang
- College of Veterinary Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Chun-Wei Shi
- College of Veterinary Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Gui-Lian Yang
- College of Veterinary Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Hai-Bin Huang
- College of Veterinary Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Jian-Zhong Wang
- College of Veterinary Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Yan-Long Jiang
- College of Veterinary Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Xin Cao
- College of Veterinary Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Nan Wang
- College of Veterinary Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Yan Zeng
- College of Veterinary Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Wen-Tao Yang
- College of Veterinary Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Chun-Feng Wang
- College of Veterinary Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
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Wu B, Li D, Bai H, Mo R, Li H, Xie J, Zhang X, Yang Y, Li H, Idris A, Li X, Feng R. Mammalian reovirus µ1 protein attenuates RIG-I and MDA5-mediated signaling transduction by blocking IRF3 phosphorylation and nuclear translocation. Mol Immunol 2024; 170:131-143. [PMID: 38663254 DOI: 10.1016/j.molimm.2024.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/04/2023] [Revised: 04/02/2024] [Accepted: 04/15/2024] [Indexed: 05/13/2024]
Abstract
Mammalian reovirus (MRV) is a non-enveloped, gene segmented double-stranded RNA (dsRNA) virus. It is an important zoonotic pathogen that infects many mammals and vertebrates that act as natural hosts and causes respiratory and digestive tract diseases. Studies have reported that RIG-I and MDA5 in the innate immune cytoplasmic RNA-sensing RIG-like receptor (RLR) signaling pathway can recognize dsRNA from MRV and promote antiviral type I interferon (IFN) responses. However, the mechanism by which many MRV-encoded proteins evade the host innate immune response remains unclear. Here, we show that exogenous μ1 protein promoted the proliferation of MRV in vitro, while knockdown of MRV μ1 protein expression by shRNA could impair MRV proliferation. Specifically, μ1 protein inhibited MRV or poly(I:C)-induced IFN-β expression, and attenuated RIG-I/MDA5-mediated signaling axis transduction during MRV infection. Importantly, we found that μ1 protein significantly decreased IFN-β mRNA expression induced by MDA5, RIG-I, MAVS, TBK1, IRF3(5D), and degraded the protein expression of exogenous MDA5, RIG-I, MAVS, TBK1 and IRF3 via the proteasomal and lysosomal pathways. Additionally, we show that μ1 protein can physically interact with MDA5, RIG-I, MAVS, TBK1, and IRF3 and attenuate the RIG-I/MDA5-mediated signaling cascades by blocking the phosphorylation and nuclear translocation of IRF3. In conclusion, our findings reveal that MRV outer capsid protein μ1 is a key factor in antagonizing RLRs signaling cascades and provide new strategies for effective prevention and treatment of MRV infection.
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Affiliation(s)
- Bei Wu
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China; College of Life science and Engineering, Northwest Minzu University, Lanzhou, China
| | - Dianyu Li
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China; College of Life science and Engineering, Northwest Minzu University, Lanzhou, China
| | - Huisheng Bai
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China; College of Life science and Engineering, Northwest Minzu University, Lanzhou, China
| | - Rongqian Mo
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China; College of Life science and Engineering, Northwest Minzu University, Lanzhou, China
| | - Hongshan Li
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China; College of Life science and Engineering, Northwest Minzu University, Lanzhou, China
| | - Jingying Xie
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China; College of Life science and Engineering, Northwest Minzu University, Lanzhou, China
| | - Xiangbo Zhang
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China; College of Life science and Engineering, Northwest Minzu University, Lanzhou, China
| | - Yanmei Yang
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China; College of Life science and Engineering, Northwest Minzu University, Lanzhou, China
| | - Huixia Li
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China; Gansu Tech Innovation Center of Animal Cell, Biomedical Research Center, Northwest Minzu University, Lanzhou, China
| | - Adi Idris
- School of Biomedical Sciences, Centre for Immunology and Infection Control, Herston, Queensland University of Technology, China; Menzies Health Institute Queensland, School of Pharmacy and Medical Science, Griffith University, Southport, Queensland, Australia
| | - Xiangrong Li
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China; Gansu Tech Innovation Center of Animal Cell, Biomedical Research Center, Northwest Minzu University, Lanzhou, China.
| | - Ruofei Feng
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China; Gansu Tech Innovation Center of Animal Cell, Biomedical Research Center, Northwest Minzu University, Lanzhou, China.
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7
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Yin L, Liu X, Yao Y, Yuan M, Luo Y, Zhang G, Pu J, Liu P. Gut microbiota-derived butyrate promotes coronavirus TGEV infection through impairing RIG-I-triggered local type I interferon responses via class I HDAC inhibition. J Virol 2024; 98:e0137723. [PMID: 38197629 PMCID: PMC10878070 DOI: 10.1128/jvi.01377-23] [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] [Academic Contribution Register] [Received: 09/05/2023] [Accepted: 12/05/2023] [Indexed: 01/11/2024] Open
Abstract
Gut microbiota-derived metabolites are important for the replication and pathogenesis of many viruses. However, the roles of bacterial metabolites in swine enteric coronavirus (SECoV) infection remain poorly understood. Recent studies show that SECoVs infection in vivo significantly alters the composition of short-chain fatty acids (SCFAs)-producing gut microbiota. This prompted us to investigate whether and how SCFAs impact SECoV infection. Employing alphacoronavirus transmissible gastroenteritis virus (TGEV), a major cause of diarrhea in piglets, as a model, we found that SCFAs, particularly butyrate, enhanced TGEV infection both in porcine intestinal epithelial cells and swine testicular (ST) cells at the late stage of viral infection. This effect depended on the inhibited productions of virus-induced type I interferon (IFN) and downstream antiviral IFN-stimulated genes (ISGs) by butyrate. Mechanistically, butyrate suppressed the expression of retinoic acid-inducible gene I (RIG-I), a key viral RNA sensor, and downstream mitochondrial antiviral-signaling (MAVS) aggregation, thereby impairing type I IFN responses and increasing TGEV replication. Using pharmacological and genetic approaches, we showed that butyrate inhibited RIG-I-induced type I IFN signaling by suppressing class I histone deacetylase (HDAC). In summary, we identified a novel mechanism where butyrate enhances TGEV infection by suppressing RIG-I-mediated type I IFN responses. Our findings highlight that gut microbiota-derived metabolites like butyrate can be exploited by SECoV to dampen innate antiviral immunity and establish infection in the intestine.IMPORTANCESwine enteric coronaviruses (SECoVs) infection in vivo alters the composition of short-chain fatty acids (SCFAs)-producing gut microbiota, but whether microbiota-derived SCFAs impact coronavirus gastrointestinal infection is largely unknown. Here, we demonstrated that SCFAs, particularly butyrate, substantially increased alphacoronavirus TGEV infection at the late stage of infection, without affecting viral attachment or internalization. Furthermore, enhancement of TGEV by butyrate depended on impeding virus-induced type I interferon (IFN) responses. Mechanistically, butyrate suppressed the cytoplasmic viral RNA sensor RIG-I expression and downstream type I IFN signaling activation by inhibiting class I HDAC, thereby promoting TGEV infection. Our work reveals novel functions of gut microbiota-derived SCFAs in enhancing enteric coronavirus infection by impairing RIG-I-dependent type I IFN responses. This implies that bacterial metabolites could be therapeutic targets against SECoV infection by modulating antiviral immunity in the intestine.
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Affiliation(s)
- Lingdan Yin
- National Key Laboratory of Veterinary Public Health Security, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Xiang Liu
- National Key Laboratory of Veterinary Public Health Security, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Yao Yao
- National Key Laboratory of Veterinary Public Health Security, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Mengqi Yuan
- National Key Laboratory of Veterinary Public Health Security, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Yi Luo
- National Key Laboratory of Veterinary Public Health Security, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Guozhong Zhang
- National Key Laboratory of Veterinary Public Health Security, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Juan Pu
- National Key Laboratory of Veterinary Public Health Security, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Pinghuang Liu
- National Key Laboratory of Veterinary Public Health Security, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
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8
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Kong W, Cheng G, Cao J, Yu J, Wang X, Xu Z. Ocular mucosal homeostasis of teleost fish provides insight into the coevolution between microbiome and mucosal immunity. MICROBIOME 2024; 12:10. [PMID: 38218870 PMCID: PMC10787490 DOI: 10.1186/s40168-023-01716-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 08/25/2023] [Accepted: 11/07/2023] [Indexed: 01/15/2024]
Abstract
BACKGROUND The visual organ plays a crucial role in sensing environmental information. However, its mucosal surfaces are constantly exposed to selective pressures from aquatic or airborne pathogens and microbial communities. Although few studies have characterized the conjunctival-associated lymphoid tissue (CALT) in the ocular mucosa (OM) of birds and mammals, little is known regarding the evolutionary origins and functions of immune defense and microbiota homeostasis of the OM in the early vertebrates. RESULTS Our study characterized the structure of the OM microbial ecosystem in rainbow trout (Oncorhynchus mykiss) and confirmed for the first time the presence of a diffuse mucosal-associated lymphoid tissue (MALT) in fish OM. Moreover, the microbial communities residing on the ocular mucosal surface contribute to shaping its immune environment. Interestingly, following IHNV infection, we observed robust immune responses, significant tissue damage, and microbial dysbiosis in the trout OM, particularly in the fornix conjunctiva (FC), which is characterized by the increase of pathobionts and a reduction of beneficial taxa in the relative abundance in OM. Critically, we identified a significant correlation between viral-induced immune responses and microbiome homeostasis in the OM, underscoring its key role in mucosal immunity and microbiota homeostasis. CONCLUSIONS Our findings suggest that immune defense and microbiota homeostasis in OM occurred concurrently in early vertebrate species, shedding light on the coevolution between microbiota and mucosal immunity. Video Abstract.
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Affiliation(s)
- Weiguang Kong
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China
| | - Gaofeng Cheng
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Jiafeng Cao
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo, 315832, China
| | - Jiaqian Yu
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China
| | - Xinyou Wang
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Zhen Xu
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China.
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9
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Dai J, Agbemabiese CA, Griffin AN, Patton JT. Rotavirus capping enzyme VP3 inhibits interferon expression by inducing MAVS degradation during viral replication. mBio 2023; 14:e0225523. [PMID: 37905816 PMCID: PMC10746195 DOI: 10.1128/mbio.02255-23] [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] [Academic Contribution Register] [Received: 08/21/2023] [Accepted: 09/22/2023] [Indexed: 11/02/2023] Open
Abstract
IMPORTANCE Rotavirus is an enteric RNA virus that causes severe dehydrating gastroenteritis in infants and young children through infection of enterocytes in the small intestine. Timely clearance of the virus demands a robust innate immune response by cells associated with the small intestine, including the expression of interferon (IFN). Previous studies have shown that some rotavirus strains suppress the production of interferon, by inducing the degradation of mitochondrial antiviral signaling (MAVS) protein and interferon regulatory factor-3 (IRF3). In this study, we have used reverse genetics to generate recombinant rotaviruses expressing compromised forms of VP3 or NSP1, or both, to explore the function of these viral proteins in the degradation of MAVS and IRF3. Our results demonstrate that VP3 is responsible for MAVS depletion in rotavirus-infected cells, and through this activity, helps to suppress IFN production. Thus, VP3 functions to support the activity of rotavirus NSP1, the major interferon antagonist of the virus.
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Affiliation(s)
- Jin Dai
- Department of Biology, Indiana University, Bloomington, Indiana, USA
| | | | - Ashley N. Griffin
- Department of Biology, Indiana University, Bloomington, Indiana, USA
| | - John T. Patton
- Department of Biology, Indiana University, Bloomington, Indiana, USA
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10
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Abstract
The gut microbiota plays a key role in host health and disease, particularly through their interactions with the immune system. Intestinal homeostasis is dependent on the symbiotic relationships between the host and the diverse gut microbiota, which is influenced by the highly co-evolved immune-microbiota interactions. The first step of the interaction between the host and the gut microbiota is the sensing of the gut microbes by the host immune system. In this review, we describe the cells of the host immune system and the proteins that sense the components and metabolites of the gut microbes. We further highlight the essential roles of pattern recognition receptors (PRRs), the G protein-coupled receptors (GPCRs), aryl hydrocarbon receptor (AHR) and the nuclear receptors expressed in the intestinal epithelial cells (IECs) and the intestine-resident immune cells. We also discuss the mechanisms by which the disruption of microbial sensing because of genetic or environmental factors causes human diseases such as the inflammatory bowel disease (IBD).
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Affiliation(s)
- Tingting Wan
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Yalong Wang
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Kaixin He
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Shu Zhu
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
- Department of Digestive Disease, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China
- Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China
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11
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Wu M, Pei Z, Long G, Chen H, Jia Z, Xia W. Mitochondrial antiviral signaling protein: a potential therapeutic target in renal disease. Front Immunol 2023; 14:1266461. [PMID: 37901251 PMCID: PMC10602740 DOI: 10.3389/fimmu.2023.1266461] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/25/2023] [Accepted: 09/26/2023] [Indexed: 10/31/2023] Open
Abstract
Mitochondrial antiviral signaling protein (MAVS) is a key innate immune adaptor on the outer mitochondrial membrane that acts as a switch in the immune signal transduction response to viral infections. Some studies have reported that MAVS mediates NF-κB and type I interferon signaling during viral infection and is also required for optimal NLRP3 inflammasome activity. Recent studies have reported that MAVS is involved in various cancers, systemic lupus erythematosus, kidney diseases, and cardiovascular diseases. Herein, we summarize the structure, activation, pathophysiological roles, and MAVS-based therapies for renal diseases. This review provides novel insights into MAVS's role and therapeutic potential in the pathogenesis of renal diseases.
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Affiliation(s)
- Meng Wu
- Department of Clinical Laboratory, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Zhiyin Pei
- Department of Clinical Laboratory, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Guangfeng Long
- Department of Clinical Laboratory, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Hongbing Chen
- Department of Clinical Laboratory, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Zhanjun Jia
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Weiwei Xia
- Department of Clinical Laboratory, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
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12
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Muslimov A, Tereshchenko V, Shevyrev D, Rogova A, Lepik K, Reshetnikov V, Ivanov R. The Dual Role of the Innate Immune System in the Effectiveness of mRNA Therapeutics. Int J Mol Sci 2023; 24:14820. [PMID: 37834268 PMCID: PMC10573212 DOI: 10.3390/ijms241914820] [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] [Academic Contribution Register] [Received: 07/13/2023] [Revised: 09/24/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
Advances in molecular biology have revolutionized the use of messenger RNA (mRNA) as a therapeutic. The concept of nucleic acid therapy with mRNA originated in 1990 when Wolff et al. reported successful expression of proteins in target organs by direct injection of either plasmid DNA or mRNA. It took decades to bring the transfection efficiency of mRNA closer to that of DNA. The next few decades were dedicated to turning in vitro-transcribed (IVT) mRNA from a promising delivery tool for gene therapy into a full-blown therapeutic modality, which changed the biotech market rapidly. Hundreds of clinical trials are currently underway using mRNA for prophylaxis and therapy of infectious diseases and cancers, in regenerative medicine, and genome editing. The potential of IVT mRNA to induce an innate immune response favors its use for vaccination and immunotherapy. Nonetheless, in non-immunotherapy applications, the intrinsic immunostimulatory activity of mRNA directly hinders the desired therapeutic effect since it can seriously impair the target protein expression. Targeting the same innate immune factors can increase the effectiveness of mRNA therapeutics for some indications and decrease it for others, and vice versa. The review aims to present the innate immunity-related 'barriers' or 'springboards' that may affect the development of immunotherapies and non-immunotherapy applications of mRNA medicines.
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Affiliation(s)
- Albert Muslimov
- Scientific Center for Translational Medicine, Sirius University of Science and Technology, Olympic Ave 1, 354340 Sirius, Russia; (V.T.); (D.S.); (V.R.); (R.I.)
- Laboratory of Nano- and Microencapsulation of Biologically Active Substances, Peter the Great St. Petersburg Polytechnic University, Polytechnicheskaya 29, 195251 St. Petersburg, Russia;
- RM Gorbacheva Research Institute, Pavlov University, L’va Tolstogo 6-8, 197022 St. Petersburg, Russia;
| | - Valeriy Tereshchenko
- Scientific Center for Translational Medicine, Sirius University of Science and Technology, Olympic Ave 1, 354340 Sirius, Russia; (V.T.); (D.S.); (V.R.); (R.I.)
| | - Daniil Shevyrev
- Scientific Center for Translational Medicine, Sirius University of Science and Technology, Olympic Ave 1, 354340 Sirius, Russia; (V.T.); (D.S.); (V.R.); (R.I.)
| | - Anna Rogova
- Laboratory of Nano- and Microencapsulation of Biologically Active Substances, Peter the Great St. Petersburg Polytechnic University, Polytechnicheskaya 29, 195251 St. Petersburg, Russia;
- Saint-Petersburg Chemical-Pharmaceutical University, Professora Popova 14, 197376 St. Petersburg, Russia
- School of Physics and Engineering, ITMO University, Lomonosova 9, 191002 St. Petersburg, Russia
| | - Kirill Lepik
- RM Gorbacheva Research Institute, Pavlov University, L’va Tolstogo 6-8, 197022 St. Petersburg, Russia;
| | - Vasiliy Reshetnikov
- Scientific Center for Translational Medicine, Sirius University of Science and Technology, Olympic Ave 1, 354340 Sirius, Russia; (V.T.); (D.S.); (V.R.); (R.I.)
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Prospekt Akad. Lavrentyeva 10, 630090 Novosibirsk, Russia
| | - Roman Ivanov
- Scientific Center for Translational Medicine, Sirius University of Science and Technology, Olympic Ave 1, 354340 Sirius, Russia; (V.T.); (D.S.); (V.R.); (R.I.)
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13
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Kwon EB, Kim SG, Kim YS, Kim B, Han SM, Lee HJ, Choi HM, Choi JG. Castanea crenata honey reduces influenza infection by activating the innate immune response. Front Immunol 2023; 14:1157506. [PMID: 37711616 PMCID: PMC10497975 DOI: 10.3389/fimmu.2023.1157506] [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] [Academic Contribution Register] [Received: 02/02/2023] [Accepted: 07/31/2023] [Indexed: 09/16/2023] Open
Abstract
Influenza is an acute respiratory disorder caused by the influenza virus and is associated with prolonged hospitalization and high mortality rates in older individuals and chronically ill patients. Vaccination is the most effective preventive strategy for ameliorating seasonal influenza. However, the vaccine is not fully effective in cases of antigenic mismatch with the viral strains circulating in the community. The emergence of resistance to antiviral drugs aggravates the situation. Therefore, developing new vaccines and antiviral drugs is essential. Castanea crenata honey (CH) is an extensively cultivated food worldwide and has been used as a nutritional supplement or herbal medicine. However, the potential anti-influenza properties of CH remain unexplored. In this study, the in vitro and in vivo antiviral effects of CH were assessed. CH significantly prevented influenza virus infection in mouse Raw264.7 macrophages. CH pretreatment inhibited the expression of the viral proteins M2, PA, and PB1 and enhanced the secretion of proinflammatory cytokines and type-I interferon (IFN)-related proteins in vitro. CH increased the expression of RIG-1, mitochondrial antiviral signaling (MAVS) protein, and IFN-inducible transmembrane protein, which interferes with virus replication. CH reduced body weight loss by 20.9%, increased survival by 60%, and decreased viral replication and inflammatory response in the lungs of influenza A virus-infected mice. Therefore, CH stimulates an antiviral response in murine macrophages and mice by preventing viral infection through the RIG-1-mediated MAVS pathway. Further investigation is warranted to understand the molecular mechanisms involved in the protective effects of CH on influenza virus infection.
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Affiliation(s)
- Eun-Bin Kwon
- Korean Medicine Application Center, Korea Institute of Oriental Medicine, Daegu, Republic of Korea
| | - Se-Gun Kim
- Department of Agricultural Biology, National Institute of Agricultural Sciences, Rural Development Administration, Wanju, Republic of Korea
| | - Young Soo Kim
- Korean Medicine Application Center, Korea Institute of Oriental Medicine, Daegu, Republic of Korea
| | - Buyun Kim
- Korean Medicine Application Center, Korea Institute of Oriental Medicine, Daegu, Republic of Korea
| | - Sang Mi Han
- Department of Agricultural Biology, National Institute of Agricultural Sciences, Rural Development Administration, Wanju, Republic of Korea
| | - Hye Jin Lee
- Department of Agricultural Biology, National Institute of Agricultural Sciences, Rural Development Administration, Wanju, Republic of Korea
| | - Hong Min Choi
- Department of Agricultural Biology, National Institute of Agricultural Sciences, Rural Development Administration, Wanju, Republic of Korea
| | - Jang-Gi Choi
- Korean Medicine Application Center, Korea Institute of Oriental Medicine, Daegu, Republic of Korea
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14
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Andersen V, Bennike TB, Bang C, Rioux JD, Hébert-Milette I, Sato T, Hansen AK, Nielsen OH. Investigating the Crime Scene-Molecular Signatures in Inflammatory Bowel Disease. Int J Mol Sci 2023; 24:11217. [PMID: 37446397 PMCID: PMC10342864 DOI: 10.3390/ijms241311217] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/31/2023] [Revised: 06/23/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
Inflammatory bowel diseases (IBD) are without cure and troublesome to manage because of the considerable diversity between patients and the lack of reliable biomarkers. Several studies have demonstrated that diet, gut microbiota, genetics and other patient factors are essential for disease occurrence and progression. Understanding the link between these factors is crucial for identifying molecular signatures that identify biomarkers to advance the management of IBD. Recent technological breakthroughs and data integration have fuelled the intensity of this research. This research demonstrates that the effect of diet depends on patient factors and gut microbial activity. It also identifies a range of potential biomarkers for IBD management, including mucosa-derived cytokines, gasdermins and neutrophil extracellular traps, all of which need further evaluation before clinical translation. This review provides an update on cutting-edge research in IBD that aims to improve disease management and patient quality of life.
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Affiliation(s)
- Vibeke Andersen
- Molecular Diagnostic and Clinical Research Unit, University Hospital of Southern Denmark, Institute of Regional Research, University of Southern Denmark, 5000 Odense, Denmark;
- Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark
| | - Tue B. Bennike
- Molecular Diagnostic and Clinical Research Unit, University Hospital of Southern Denmark, Institute of Regional Research, University of Southern Denmark, 5000 Odense, Denmark;
- Medical Microbiology and Immunology, Department of Health Science and Technology, Aalborg University, 9000 Aalborg, Denmark
| | - Corinna Bang
- Institute for Clinical Molecular Biology, Christian-Albrecht’s University, 24105 Kiel, Germany;
| | - John D. Rioux
- Department of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada; (J.D.R.); (I.H.-M.)
- Montreal Heart Institute Research Institute, Montreal, QC H1T 1C8, Canada
| | - Isabelle Hébert-Milette
- Department of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada; (J.D.R.); (I.H.-M.)
- Montreal Heart Institute Research Institute, Montreal, QC H1T 1C8, Canada
| | - Toshiro Sato
- Department of Gastroenterology, Keio University School of Medicine, Tokyo 160-8582, Japan;
| | - Axel K. Hansen
- Experimental Animal Models, Department of Veterinary and Animal Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark;
| | - Ole H. Nielsen
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, 2730 Herlev, Denmark
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15
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Liu XY, Wang MY, Zhang Q, Kong XY, Wang H, Li DD, Pang LL, Duan ZJ. The induction and suppression of type I and type III interferons by human group H rotavirus. Virology 2023; 581:26-33. [PMID: 36848734 DOI: 10.1016/j.virol.2023.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/10/2023] [Revised: 02/15/2023] [Accepted: 02/17/2023] [Indexed: 02/24/2023]
Abstract
Group H Rotavirus (RVH) is associated with human diarrhea gastroenteritis. The interferon (IFN) response induced by RVH remains unclear. In this study, we first studied the characteristic feature of RVH and found J19 strain of RVH grew less efficiently compared with the G6P1 strain of RVA. Next, we found that infection with the J19 virus resulted in the secretion of IFN-λ1, but not IFN-β, while both IFN-β and IFN-λ1 could inhibit J19 replication significantly in Caco-2 cells. NSP1 played an important role in the suppression of type I and type III IFN response, and NSP5 protein significantly inhibited activation of IFN-λ1. J19 NSP1 suppressed the induction of IFN-β obviously than G6P1 NSP1, while G6P1 NSP1 reduced IFN-λ1 induction to the greatest extent compared with G9P8, Wa, and J19 NSP1s. Our studies reveal the propagation feature of RVH and interferon induction and suppression by group H rotavirus.
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Affiliation(s)
- Xin-Yi Liu
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, 102206, China; School of Public Health, Gansu University of Chinese Medicine, Lanzhou, 730000, China
| | - Ming-Yue Wang
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, 102206, China; School of Public Health, Gansu University of Chinese Medicine, Lanzhou, 730000, China
| | - Qing Zhang
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, 102206, China
| | - Xiang-Yu Kong
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, 102206, China
| | - Hong Wang
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, 102206, China
| | - Dan-di Li
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, 102206, China
| | - Li-Li Pang
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, 102206, China.
| | - Zhao-Jun Duan
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, 102206, China.
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16
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Hu X, Wu X, Ding Z, Chen Z, Wu H. Characterization and functional analysis of chicken dsRNA binding protein hnRNPU. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2023; 138:104521. [PMID: 36044969 DOI: 10.1016/j.dci.2022.104521] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 06/02/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 06/15/2023]
Abstract
In mammals, heterogeneous ribonucleoprotein U (hnRNPU), also named as nuclear matrix protein-nuclear scaffold attachment factor (SAFA), was originally identified as a DNA/RNA interactor protein. It has been reported that human hnRNPU facilitates IFN-β generation after vesicular stomatitis virus (VSV) infection. Nevertheless, the role of chicken hnRNPU (chhnRNPU) in IFN-β regulation as well as in infectious bursal diseases virus (IBDV) replication is still unclear. Here, we found that chhnRNPU inhibits IFN-β production via interacting with MDA5 and MAVS, and facilitates IBDV replication via associating with genomic dsRNA of IBDV. Firstly, chicken hnRNPU (chhnRNPU) was widely expressed in different tissues of chickens and was distributed in the nucleus of DF-1 cells. Overexpression of chhnRNPU significantly suppresses IFN-β promoter activities induced by MDA5 and MAVS. Additionally, immunoprecipitated by dsRNA antibodies, which followed LC-MS analysis demonstrate that chhnRNPU is a partner of viral genomic dsRNA. chhnRNPU is translocated from nucleus to cytosol to co-localize with replication complex of IBDV after IBDV infection. Over-expression of chhnRNPU significantly promotes IBDV replication, which was determined by western blotting, qRT-PCR and TCID50 assay. Furthermore, knock down chhnRNPU by siRNA remarkably facilitates IFN-β production, and inhibits IBDV proliferation. These data collectively reveal that chhnRNPU positively regulates IBDV replication via negatively regulating IFN-β response.
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Affiliation(s)
- Xifeng Hu
- Department of Veterinary Preventive Medicine, College of Animal Science and Technology, Jiangxi Agricultural University, Zhimin Street, Qingshan Lake, Nanchang, 330045, PR China; Jiangxi Provincial Key Laboratory for Animal Science and Technology, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, 330045, PR China
| | - Xiangdong Wu
- Department of Veterinary Preventive Medicine, College of Animal Science and Technology, Jiangxi Agricultural University, Zhimin Street, Qingshan Lake, Nanchang, 330045, PR China; Jiangxi Provincial Key Laboratory for Animal Science and Technology, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, 330045, PR China
| | - Zhen Ding
- Department of Veterinary Preventive Medicine, College of Animal Science and Technology, Jiangxi Agricultural University, Zhimin Street, Qingshan Lake, Nanchang, 330045, PR China; Jiangxi Provincial Key Laboratory for Animal Science and Technology, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, 330045, PR China
| | - Zheng Chen
- Department of Veterinary Preventive Medicine, College of Animal Science and Technology, Jiangxi Agricultural University, Zhimin Street, Qingshan Lake, Nanchang, 330045, PR China; Jiangxi Provincial Key Laboratory for Animal Science and Technology, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, 330045, PR China
| | - Huansheng Wu
- Department of Veterinary Preventive Medicine, College of Animal Science and Technology, Jiangxi Agricultural University, Zhimin Street, Qingshan Lake, Nanchang, 330045, PR China; Jiangxi Provincial Key Laboratory for Animal Science and Technology, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, 330045, PR China.
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17
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Mochochoko BM, Pohl CH, O’Neill HG. Candida albicans-enteric viral interactions-The prostaglandin E 2 connection and host immune responses. iScience 2022; 26:105870. [PMID: 36647379 PMCID: PMC9839968 DOI: 10.1016/j.isci.2022.105870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/25/2022] Open
Abstract
The human microbiome comprises trillions of microorganisms residing within different mucosal cavities and across the body surface. The gut microbiota modulates host susceptibility to viral infections in several ways, and microbial interkingdom interactions increase viral infectivity within the gut. Candida albicans, a frequently encountered fungal species in the gut, produces highly structured biofilms and eicosanoids such as prostaglandin E2 (PGE2), which aid in viral protection and replication. These biofilms encompass viruses and provide a shield from antiviral drugs or the immune system. PGE2 is a key modulator of active inflammation with the potential to regulate interferon signaling upon microbial invasion or viral infections. In this review, we raise the perspective of gut interkingdom interactions involving C. albicans and enteric viruses, with a special focus on biofilms, PGE2, and viral replication. Ultimately, we discuss the possible implications of C. albicans-enteric virus associations on host immune responses, particularly the interferon signaling pathway.
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Affiliation(s)
- Bonang M. Mochochoko
- Department of Microbiology and Biochemistry, University of the Free State, Bloemfontein, 9301, South Africa
| | - Carolina H. Pohl
- Department of Microbiology and Biochemistry, University of the Free State, Bloemfontein, 9301, South Africa,Corresponding author
| | - Hester G. O’Neill
- Department of Microbiology and Biochemistry, University of the Free State, Bloemfontein, 9301, South Africa,Corresponding author
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18
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Dai J, Yi G, Philip AA, Patton JT. Rotavirus NSP1 Subverts the Antiviral Oligoadenylate Synthetase-RNase L Pathway by Inducing RNase L Degradation. mBio 2022; 13:e0299522. [PMID: 36413023 PMCID: PMC9765674 DOI: 10.1128/mbio.02995-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/26/2022] [Accepted: 11/01/2022] [Indexed: 11/23/2022] Open
Abstract
The interferon (IFN)-inducible 2',5'-oligoadenylate synthetase (OAS)-RNase L pathway plays a critical role in antiviral immunity. Group A rotaviruses, including the simian SA11 strain, inhibit this pathway through two activities: an E3-ligase related activity of NSP1 that degrades proteins necessary for IFN signaling, and a phosphodiesterase (PDE) activity of VP3 that hydrolyzes the RNase L-activator 2',5'-oligoadenylate. Unexpectedly, we found that a recombinant (r) SA11 double mutant virus deficient in both activities (rSA11-VP3H797R-NSP1ΔC17) retained the ability to prevent RNase L activation. Mass spectrometry led to the discovery that NSP1 interacts with RNase L in rSA11-infected HT29 cells. This interaction was confirmed through copulldown assay of cells transiently expressing NSP1 and RNase L. Immunoblot analysis showed that infection with wild-type rSA11 virus, rSA11-VP3H797R-NSP1ΔC17 double mutant virus, or single mutant forms of the latter virus all resulted in the depletion of endogenous RNase L. The loss of RNase L was reversed by addition of the neddylation inhibitor MLN4924, but not the proteasome inhibitor MG132. Analysis of additional mutant forms of rSA11 showed that RNase L degradation no longer occurred when either the N-terminal RING domain of NSP1 was mutated or the C-terminal 98 amino acids of NSP1 were deleted. The C-terminal RNase L degradation domain is positioned upstream and is functionally independent of the NSP1 domain necessary for inhibiting IFN expression. Our studies reveal a new role for NSP1 and its E3-ligase related activity as an antagonist of RNase L and uncover a novel virus-mediated strategy of inhibiting the OAS-RNase L pathway. IMPORTANCE For productive infection, rotavirus and other RNA viruses must suppress interferon (IFN) signaling and the expression of IFN-stimulated antiviral gene products. Particularly important is inhibiting the interferon (IFN)-inducible 2',5'-oligoadenylate synthetase (OAS)-RNase L pathway, as activated RNase L can direct the nonspecific degradation of viral and cellular RNAs, thereby blocking viral replication and triggering cell death pathways. In this study, we have discovered that the simian SA11 strain of rotavirus employs a novel strategy of inhibiting the OAS-RNase L pathway. This strategy is mediated by SA11 NSP1, a nonstructural protein that hijacks E3 cullin-RING ligases, causing the ubiquitination and degradation of host proteins essential for IFN induction. Our analysis shows that SA11 NSP1 also recognizes and causes the ubiquitination of RNase L, an activity resulting in depletion of endogenous RNase L. These data raise the possibility of using therapeutics targeting cellular E3 ligases to control rotavirus infections.
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Affiliation(s)
- Jin Dai
- Department of Biology, Indiana University, Bloomington, Indiana, USA
| | - Guanghui Yi
- Department of Biology, Indiana University, Bloomington, Indiana, USA
| | - Asha A. Philip
- Department of Biology, Indiana University, Bloomington, Indiana, USA
| | - John T. Patton
- Department of Biology, Indiana University, Bloomington, Indiana, USA
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Nagaraj S, Stankiewicz-Drogon A, Darzynkiewicz E, Grzela R. RNA sensor response in HeLa cells for transfected mRNAs prepared in vitro by SP6 and HiT7 RNA polymerases: A comparative study. Front Bioeng Biotechnol 2022; 10:1017934. [PMID: 36406230 PMCID: PMC9669293 DOI: 10.3389/fbioe.2022.1017934] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/16/2022] [Accepted: 10/19/2022] [Indexed: 08/18/2023] Open
Abstract
In vitro transcribed (IVT) synthetic mRNAs are in high demand due to their attractive bench to clinic translational processes. Mainly, the procedure to make IVT mRNA using bacteriophage RNA polymerases (RNAP) is relatively uncomplicated and scalable to produce large quantities in a short time period. However, IVT mRNA preparations are accompanied by contaminants such as double-stranded RNA (dsRNA) as by-products that elicit undesired cellular immune responses upon transfections. Therefore, removing dsRNA contaminants is critical in IVT mRNA preparations for therapeutic applications. One such method to minimize dsRNA contaminants is to use genetically modified thermostable bacteriophage polymerase, HiT7 RNAP that performs IVT reaction at a higher temperature than typically used. However, the cellular RNA sensor response for IVT mRNA preparations by HiT7 RNAP is not characterized. Here, we compared the cellular RNA sensor response for mRNAs prepared by HiT7 RNAP (at 50°C) and SP6 RNAP (at 37°C) in HeLa cells. We show that IVT mRNA preparations by HiT7 RNAP reduced the dsRNA levels and dsRNA specific RNA sensor response (retinoic acid-inducible gene I, RIG-I and melanoma differentiation-associated 5, MDA5) compared to the IVT mRNA preparations by SP6 RNAP. Similarly, the incorporation of pseudouridine nucleotides instead of uridine nucleotides reduced dsRNA sensor response and increased the mRNA translation. Overall, the least dsRNA mediated RNA sensor response is observed when mRNA is synthesized by HiT7 RNAP and incorporated with pseudouridine nucleotides.
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Affiliation(s)
- Siranjeevi Nagaraj
- Interdisciplinary Laboratory of Molecular Biology and Biophysics, Centre of New Technologies, University of WarsawWarsaw, Poland
| | - Anna Stankiewicz-Drogon
- Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of WarsawWarsaw, Poland
| | - Edward Darzynkiewicz
- Interdisciplinary Laboratory of Molecular Biology and Biophysics, Centre of New Technologies, University of WarsawWarsaw, Poland
- Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of WarsawWarsaw, Poland
| | - Renata Grzela
- Interdisciplinary Laboratory of Molecular Biology and Biophysics, Centre of New Technologies, University of WarsawWarsaw, Poland
- Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of WarsawWarsaw, Poland
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Kumar D, Shepherd FK, Springer NL, Mwangi W, Marthaler DG. Rotavirus Infection in Swine: Genotypic Diversity, Immune Responses, and Role of Gut Microbiome in Rotavirus Immunity. Pathogens 2022; 11:pathogens11101078. [PMID: 36297136 PMCID: PMC9607047 DOI: 10.3390/pathogens11101078] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/08/2022] [Revised: 09/13/2022] [Accepted: 09/17/2022] [Indexed: 11/16/2022] Open
Abstract
Rotaviruses (RVs) are endemic in swine populations, and all swine herds certainly have a history of RV infection and circulation. Rotavirus A (RVA) and C (RVC) are the most common among all RV species reported in swine. RVA was considered most prevalent and pathogenic in swine; however, RVC has been emerging as a significant cause of enteritis in newborn piglets. RV eradication from swine herds is not practically achievable, hence producers’ mainly focus on minimizing the production impact of RV infections by reducing mortality and diarrhea. Since no intra-uterine passage of immunoglobulins occur in swine during gestation, newborn piglets are highly susceptible to RV infection at birth. Boosting lactogenic immunity in gilts by using vaccines and natural planned exposure (NPE) is currently the only way to prevent RV infections in piglets. RVs are highly diverse and multiple RV species have been reported from swine, which also contributes to the difficulties in preventing RV diarrhea in swine herds. Human RV-gut microbiome studies support a link between microbiome composition and oral RV immunogenicity. Such information is completely lacking for RVs in swine. It is not known how RV infection affects the functionality or structure of gut microbiome in swine. In this review, we provide a detailed overview of genotypic diversity of swine RVs, host-ranges, innate and adaptive immune responses to RVs, homotypic and heterotypic immunity to RVs, current methods used for RV management in swine herds, role of maternal immunity in piglet protection, and prospects of investigating swine gut microbiota in providing immunity against rotaviruses.
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Affiliation(s)
- Deepak Kumar
- Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA
- Correspondence: (D.K.); (W.M.); (D.G.M.); Tel.: +1-804-503-1241 (D.K.)
| | - Frances K Shepherd
- Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55108, USA
| | - Nora L. Springer
- Clinical Pathology, Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA
| | - Waithaka Mwangi
- Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA
- Correspondence: (D.K.); (W.M.); (D.G.M.); Tel.: +1-804-503-1241 (D.K.)
| | - Douglas G. Marthaler
- Indical Inc., 1317 Edgewater Dr #3722, Orlando, FL 32804, USA
- Correspondence: (D.K.); (W.M.); (D.G.M.); Tel.: +1-804-503-1241 (D.K.)
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Ayechu-Muruzabal V, Poelmann B, Berends AJ, Kettelarij N, Garssen J, van’t Land B, Willemsen LEM. Human Milk Oligosaccharide 2'-Fucosyllactose Modulates Local Viral Immune Defense by Supporting the Regulatory Functions of Intestinal Epithelial and Immune Cells. Int J Mol Sci 2022; 23:ijms231810958. [PMID: 36142892 PMCID: PMC9506168 DOI: 10.3390/ijms231810958] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/15/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
Human milk contains bioactive components that provide protection against viral infections in early life. In particular, intestinal epithelial cells (IEC) have key regulatory roles in the prevention of enteric viral infections. Here we established an in vitro model to study the modulation of host responses against enteric viruses mimicked by poly I:C (pIC). The effects of 2′-fucosyllactose (2′FL), abundantly present in human milk, were studied on IEC and/or innate immune cells, and the subsequent functional response of the adaptive immune cells. IEC were pre-incubated with 2′FL and stimulated with naked or Lyovec™-complexed pIC (LV-pIC). Additionally, monocyte-derived dendritic cells (moDC) alone or in co-culture with IEC were stimulated with LV-pIC. Then, conditioned-moDC were co-cultured with naïve CD4+ T helper (Th)-cells. IEC stimulation with naked or LV-pIC promoted pro-inflammatory IL-8, CCL20, GROα and CXCL10 cytokine secretion. However, only exposure to LV-pIC additionally induced IFNβ, IFNλ1 and CCL5 secretion. Pre-incubation with 2′FL further increased pIC induced CCL20 secretion and LV-pIC induced CXCL10 secretion. LV-pIC-exposed IEC/moDC and moDC cultures showed increased secretion of IL-8, GROα, IFNλ1 and CXCL10, and in the presence of 2′FL galectin-4 and -9 were increased. The LV-pIC-exposed moDC showed a more pronounced secretion of CCL20, CXCL10 and CCL5. The moDC from IEC/moDC cultures did not drive T-cell development in moDC/T-cell cultures, while moDC directly exposed to LV-pIC secreted Th1 driving IL-12p70 and promoted IFNγ secretion by Th-cells. Hereby, a novel intestinal model was established to study mucosal host-defense upon a viral trigger. IEC may support intestinal homeostasis, regulating local viral defense which may be modulated by 2′FL. These results provide insights regarding the protective capacity of human milk components in early life.
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Affiliation(s)
- Veronica Ayechu-Muruzabal
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
| | - Bente Poelmann
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
| | - Alinda J. Berends
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
| | | | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
- Danone Nutricia Research, 3584 CT Utrecht, The Netherlands
| | - Belinda van’t Land
- Danone Nutricia Research, 3584 CT Utrecht, The Netherlands
- Center for Translational Immunology, The Wilhelmina Children’s Hospital, University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands
| | - Linette E. M. Willemsen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
- Correspondence:
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Mature Rotavirus Particles Contain Equivalent Amounts of 7meGpppG-Capped and Noncapped Viral Positive-Sense RNAs. J Virol 2022; 96:e0115122. [PMID: 36000838 PMCID: PMC9472601 DOI: 10.1128/jvi.01151-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/20/2022] Open
Abstract
Viruses have evolved different strategies to overcome their recognition by the host innate immune system. The addition of caps at their 5' RNA ends is an efficient mechanism not only to ensure escape from detection by the innate immune system but also to ensure the efficient synthesis of viral proteins. Rotavirus mRNAs contain a type 1 cap structure at their 5' end that is added by the viral capping enzyme VP3, which is a multifunctional protein with all the enzymatic activities necessary to add the cap and also functions as an antagonist of the 2'-5'-oligoadenylate synthetase (OAS)/RNase L pathway. Here, the relative abundances of capped and noncapped viral RNAs during the replication cycle of rotavirus were determined. We found that both classes of rotaviral plus-sense RNAs (+RNAs) were encapsidated and that they were present in a 1:1 ratio in the mature infectious particles. The capping of viral +RNAs was dynamic, since different ratios of capped and noncapped RNAs were detected at different times postinfection. Similarly, when the relative amounts of capped and uncapped viral +RNAs produced in an in vitro transcription system were determined, we found that the proportions were very similar to those in the mature viral particles and in infected cells, suggesting that the capping efficiency of VP3, both in vivo and in vitro, might be close to 50%. Unexpectedly, when the effect of simultaneously knocking down the expression of VP3 and RNase L on the cap status of viral +RNAs was evaluated, we found that, even though at late times postinfection there was an increased proportion of capped viral RNAs in infected cells, the viral particles isolated from this condition contained equal ratios of capped and noncapped viral RNA, suggesting that there might be selective packaging of capped and noncapped RNAs. IMPORTANCE Rotaviruses have a genome composed of 11 segments of double-stranded RNA. Whether all 5' ends of the positive-sense genomic RNAs contained in the mature viral particles are modified by a cap structure is unknown. In this work, we characterized the relative proportions of capped and noncapped viral RNAs in rotavirus-infected cells and in viral particles by using a direct quantitative assay. We found that, independent of the relative proportions of capped/noncapped RNAs present in rotavirus-infected cells, there were similar proportions of these two kinds of 5'-modified positive-sense RNAs in the viral particles.
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23
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Li YJ, Chen CY, Yang JH, Chiu YF. Modulating cholesterol-rich lipid rafts to disrupt influenza A virus infection. Front Immunol 2022; 13:982264. [PMID: 36177026 PMCID: PMC9513517 DOI: 10.3389/fimmu.2022.982264] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/30/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Influenza A virus (IAV) is widely disseminated across different species and can cause recurrent epidemics and severe pandemics in humans. During infection, IAV attaches to receptors that are predominantly located in cell membrane regions known as lipid rafts, which are highly enriched in cholesterol and sphingolipids. Following IAV entry into the host cell, uncoating, transcription, and replication of the viral genome occur, after which newly synthesized viral proteins and genomes are delivered to lipid rafts for assembly prior to viral budding from the cell. Moreover, during budding, IAV acquires an envelope with embedded cholesterol from the host cell membrane, and it is known that decreased cholesterol levels on IAV virions reduce infectivity. Statins are commonly used to inhibit cholesterol synthesis for preventing cardiovascular diseases, and several studies have investigated whether such inhibition can block IAV infection and propagation, as well as modulate the host immune response to IAV. Taken together, current research suggests that there may be a role for statins in countering IAV infections and modulating the host immune response to prevent or mitigate cytokine storms, and further investigation into this is warranted.
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Affiliation(s)
- Yu-Jyun Li
- Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Chi-Yuan Chen
- Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan
| | - Jeng-How Yang
- Division of Infectious Diseases, Department of Medicine, Chang Gung Memorial Hospital, New Taipei, Taiwan
| | - Ya-Fang Chiu
- Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
- Research Center for Emerging Viral Infections, Chang Gung University, Taoyuan, Taiwan
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
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24
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Abstract
Rotaviruses represent one of the most successful pathogens in the world, with high infectivity and efficient transmission between the young of many animal species, including humans. To overcome host defenses, rotaviruses have evolved a plethora of strategies to effectively evade the innate immune response, establish initial infection in the small intestine, produce progeny, and shed into the environment. Previously, studying the roles and relative contributions of specific rotaviral factors in innate immune evasion had been challenging without a plasmid-only reverse genetics system. Although still in its infancy, current reverse genetics technology will help address important research questions regarding rotavirus innate immune evasion, host range restriction, and viral pathogenesis. In this review, we summarize the current knowledge about the antiviral host innate immune defense mechanisms, countermeasures of rotavirus-encoded factors, and strategies to better understand these interactions using the rotavirus reverse genetics system.
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Affiliation(s)
- Avan Antia
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Amanda N. Pinski
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Siyuan Ding
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA
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25
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Zhao C, Han Y, Wang C, Ren M, Hu Q, Gu Y, Ye P, Li S, Jin E. Transcriptome Profiling of Duodenum Reveals the Importance of Boron Supplementation in Modulating Immune Activities in Rats. Biol Trace Elem Res 2022; 200:3762-3773. [PMID: 34773147 DOI: 10.1007/s12011-021-02983-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 09/01/2021] [Accepted: 10/17/2021] [Indexed: 12/13/2022]
Abstract
As an essential trace element, appropriate boron supplementation can promote immune function of animals. To illustrate the effects of boron in a rat model, RNA-Seq was conducted for the RNA from duodenum after treatment with different concentration of boron in which boron was given in the form of boric acid. More than 47 million reads were obtained in 0, 10, and 320 mg/L boron (0, 57.21, and 1830.66 mg/L boric acid) treatment groups that produced 58 965 402, 48 607 328, and 46 760 660 clean reads, respectively. More than 95% of the clean reads were successfully matched to the rat reference genome and assembled to generate 32 662 transcripts. A total of 624 and 391 differentially expressed candidate genes (DEGs) were found between 0 vs.10 and 0 vs. 320 mg/L boron comparison groups. We also identified transcription start site, transcription terminal site, and skipped exons as the main alternative splicing events. GO annotations revealed most of DEGs were involved in the regulation of immune activity. The DEGs were enriched in influenza A, herpes simplex infection, cytosolic DNA-sensing pathway, and antigen processing and presentation signaling pathways. The expression levels of genes enriched in these signaling pathways indicate that lower doses of boron could achieve better effects on promoting immune response in the duodenum. These effects on the immune system appear to be mediated via altering the expression patterns of genes involved in the related signaling pathways in a dose-dependent pattern. These data provide more insights into the molecular mechanisms of immune regulation in rats in response to dietary boron treatment.
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Affiliation(s)
- Chunfang Zhao
- College of Animal Science, Anhui Science and Technology University, No. 9 Donghua Road, Fengyang County, Chuzhou, Anhui Province, China
- Anhui Province Key Laboratory of Animal Nutritional Regulation and Health, No. 9, Donghua Road, Fengyang County, Chuzhou, Anhui Province, China
| | - Yujiao Han
- College of Animal Science, Anhui Science and Technology University, No. 9 Donghua Road, Fengyang County, Chuzhou, Anhui Province, China
- Anhui Province Key Laboratory of Animal Nutritional Regulation and Health, No. 9, Donghua Road, Fengyang County, Chuzhou, Anhui Province, China
| | - Chenfang Wang
- College of Life and Health Science, Anhui Science and Technology University, No. 9, Donghua Road, Fengyang County, Chuzhou, Anhui Province, China
| | - Man Ren
- College of Animal Science, Anhui Science and Technology University, No. 9 Donghua Road, Fengyang County, Chuzhou, Anhui Province, China
- Anhui Province Key Laboratory of Animal Nutritional Regulation and Health, No. 9, Donghua Road, Fengyang County, Chuzhou, Anhui Province, China
| | - Qianqian Hu
- College of Animal Science, Anhui Science and Technology University, No. 9 Donghua Road, Fengyang County, Chuzhou, Anhui Province, China
- Anhui Province Key Laboratory of Animal Nutritional Regulation and Health, No. 9, Donghua Road, Fengyang County, Chuzhou, Anhui Province, China
| | - Youfang Gu
- College of Animal Science, Anhui Science and Technology University, No. 9 Donghua Road, Fengyang County, Chuzhou, Anhui Province, China
- Anhui Province Key Laboratory of Animal Nutritional Regulation and Health, No. 9, Donghua Road, Fengyang County, Chuzhou, Anhui Province, China
| | - Pengfei Ye
- College of Animal Science, Anhui Science and Technology University, No. 9 Donghua Road, Fengyang County, Chuzhou, Anhui Province, China
- Anhui Province Key Laboratory of Animal Nutritional Regulation and Health, No. 9, Donghua Road, Fengyang County, Chuzhou, Anhui Province, China
| | - Shenghe Li
- College of Animal Science, Anhui Science and Technology University, No. 9 Donghua Road, Fengyang County, Chuzhou, Anhui Province, China.
- Anhui Province Key Laboratory of Animal Nutritional Regulation and Health, No. 9, Donghua Road, Fengyang County, Chuzhou, Anhui Province, China.
| | - Erhui Jin
- College of Animal Science, Anhui Science and Technology University, No. 9 Donghua Road, Fengyang County, Chuzhou, Anhui Province, China.
- Anhui Province Key Laboratory of Animal Nutritional Regulation and Health, No. 9, Donghua Road, Fengyang County, Chuzhou, Anhui Province, China.
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Abstract
Mammalian orthoreovirus (reovirus) is a double-stranded RNA (dsRNA) virus which encapsidates its 10 genome segments within a double-layered viral particle. Reovirus infection triggers an antiviral response in host cells which serves to limit viral replication. This antiviral response is initiated by recognition of the incoming viral genome by host sensors present in the cytoplasm. However, how host sensors gain access to the reovirus genome is unclear, as this dsRNA is protected by the viral particle proteins throughout infection. To initiate infection, reovirus particles are endocytosed and the outer viral particle layer is disassembled through the action of host proteases. This disassembly event is required for viral escape into the cytoplasm to begin replication. We show that endosomal proteases are required even late in infection, when disassembly is complete, to induce an immune response to reovirus. Additionally, counter to dogma, our data demonstrate that at least some viral dsRNA genome is exposed and detectable during entry. We hypothesize that some proportion of reovirus particles remain trapped within endosomes, allowing for the breakdown of these particles and release of their genome. We show that rapidly uncoating mutants escape the endosome more rapidly and induce a diminished immune response. Further, we show that particles entering through dynamin-independent pathways evade detection by host sensors. Overall, our data provide new insight into how genomes from entering reovirus particles are detected by host cells. IMPORTANCE Viruses must infect host cells to replicate, often killing the host cell in the process. However, hosts can activate defenses to limit viral replication and protect the organism. To trigger these host defenses to viral infections, host cells must first recognize that they are infected. Mammalian orthoreovirus (reovirus) is a model system used to study host-virus interactions. This study identifies aspects of host and virus biology which determine the capacity of host cells to detect infection. Notably, entry of reovirus into host cells plays a critical role in determining the magnitude of immune response triggered during infection. Mutants of reovirus which can enter cells more rapidly are better at avoiding detection by the host. Additionally, reovirus can enter cells through multiple routes. Entry through some of these routes also helps reovirus evade detection.
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Wang J, Lin Z, Liu Q, Fu F, Wang Z, Ma J, Wang H, Yan Y, Cheng Y, Sun J. Bat Employs a Conserved MDA5 Gene to Trigger Antiviral Innate Immune Responses. Front Immunol 2022; 13:904481. [PMID: 35677039 PMCID: PMC9168228 DOI: 10.3389/fimmu.2022.904481] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/25/2022] [Accepted: 04/22/2022] [Indexed: 11/13/2022] Open
Abstract
Bats are important hosts for various zoonotic viral diseases. However, they rarely show signs of disease infection with such viruses. As the first line for virus control, the innate immune system of bats attracted our full attention. In this study, the Tadarida brasiliensis MDA5 gene (batMDA5), a major sensor for anti-RNA viral infection, was first cloned, and its biological functions in antiviral innate immunity were identified. Bioinformatics analysis shows that the amino acid sequence of batMDA5 is poorly conserved among species, and it is evolutionarily closer to humans. The mRNA of batMDA5 was significantly upregulated in Newcastle disease virus (NDV), avian influenza virus (AIV), and vesicular stomatitis virus (VSV)-infected bat TB 1 Lu cells. Overexpression of batMDA5 could activate IFNβ and inhibit vesicular stomatitis virus (VSV-GFP) replication in TB 1 Lu cells, while knockdown of batMDA5 yielded the opposite result. In addition, we found that the CARD domain was essential for MDA5 to activate IFNβ by constructing MDA5 domain mutant plasmids. These results indicated that bat employs a conserved MDA5 gene to trigger anti-RNA virus innate immune response. This study helps understand the biological role of MDA5 in innate immunity during evolution.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Jianhe Sun
- *Correspondence: Jianhe Sun, ; Yuqiang Cheng,
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28
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Mechanisms involved in controlling RNA virus-induced intestinal inflammation. Cell Mol Life Sci 2022; 79:313. [PMID: 35604464 PMCID: PMC9125963 DOI: 10.1007/s00018-022-04332-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/31/2022] [Revised: 03/10/2022] [Accepted: 04/27/2022] [Indexed: 12/24/2022]
Abstract
Gastroenteritis is inflammation of the lining of stomach and intestines and causes significant morbidity and mortality worldwide. Many viruses, especially RNA viruses are the most common cause of enteritis. Innate immunity is the first line of host defense against enteric RNA viruses and virus-induced intestinal inflammation. The first layer of defense against enteric RNA viruses in the intestinal tract is intestinal epithelial cells (IECs), dendritic cells and macrophages under the intestinal epithelium. These innate immune cells express pathogen-recognition receptors (PRRs) for recognizing enteric RNA viruses through sensing viral pathogen-associated molecular patterns (PAMPs). As a result of this recognition type I interferon (IFN), type III IFN and inflammasome activation occurs, which function cooperatively to clear infection and reduce viral-induced intestinal inflammation. In this review, we summarize recent findings about mechanisms involved in enteric RNA virus-induced intestinal inflammation. We will provide an overview of the enteric RNA viruses, their RNA sensing mechanisms by host PRRs, and signaling pathways triggered by host PRRs, which shape the intestinal immune response to maintain intestinal homeostasis.
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29
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Association of Gut Microbiota with Inflammatory Bowel Disease and COVID-19 Severity: A Possible Outcome of the Altered Immune Response. Curr Microbiol 2022; 79:184. [PMID: 35508737 PMCID: PMC9068506 DOI: 10.1007/s00284-022-02877-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/06/2021] [Accepted: 04/12/2022] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease could be induced by SARS-CoV-2, involved in alteration of gut microbiota during the respiratory viral infection. Presence of viral RNA in fecal samples for longer period, even after the clearance of the virus from respiratory tract, is suggestive of dysbiosis leading to the poor prognosis of COVID-19 in hospitalized patients. Gut microbiome (GM) plays a significant role to stimulate the modulated antiviral immune response against invading pathogens regulating the physiological homeostasis. GM profile of COVID-19 patients has revealed the drastic depletion of dominant families of commensals in the gut such as, Bacteroidaceae, Lachnospiraceae and Ruminococcaceae to be replaced with Enterococcus, Staphylococcus, Streptococcus, Serratia etc. Immune dysfunction of Th1–Th17 cells along gut-lung axis impairs the mucosal lining translocating the microorganisms including commensals and metabolites to other body organs like lungs, brain, kidney through circulation. These events may cause hyper inflammations associated with excessive secretion of cytokines and chemokines to form the cytokine storm causing ARDS. Gut virome could interact with microbiome and immune cells, help establishing the antiviral immune signaling, important for health maintenance/ or in disease progression. Essentially, these immunological strategies are needed to use in future prospective therapeutics to control the severity events.
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Muleta KG, Ulmert I, Hamza KH, van Dijl S, Nakawesi J, Lahl K. Rotavirus-Induced Expansion of Antigen-Specific CD8 T Cells Does Not Require Signaling via TLR3, MyD88 or the Type I Interferon Receptor. Front Immunol 2022; 13:814491. [PMID: 35464475 PMCID: PMC9022177 DOI: 10.3389/fimmu.2022.814491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/13/2021] [Accepted: 03/17/2022] [Indexed: 11/13/2022] Open
Abstract
Rotavirus (RV) infection induces strong adaptive immunity. While protection from reinfection requires humoral immunity, initial clearance of infection depends on cytotoxic CD8 T cells. Type I classical dendritic cells (cDC1) excel at CD8 T cell induction through cross-presentation and are essential for optimal cytotoxicity towards RV. Upon sensing of infection-induced innate immune signals through pattern recognition receptors (PRRs), cumulating in autocrine type I interferon (IFN) signaling, cDC1 mature and migrate to the draining lymph nodes (LNs), where they prime adaptive immune cells. To analyze which PRR pathways lead to robust cytotoxicity in the context of RV infection, we measured RV-specific CD8 T cell priming in mice deficient for Toll-like receptor 3 (TLR3), recognizing double-stranded RNA, or for MyD88, the adapter for all other TLRs and IL-1 family cytokines. Individual TLR3- and MyD88-mediated signaling was not required for the priming of CD8 T cell responses to RV and neither deficiency impacted on RV clearance. Surprisingly, the accumulation of RV-specific CD8 T cells was also not altered in the absence of type I IFN signaling, while their ability to produce IFNγ and granzyme were blunted. Together, this suggests a substantial level of redundancy in the sensing of RV infection and the translation of signals into protective CD8 T cell immunity.
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Affiliation(s)
| | - Isabel Ulmert
- Section for Experimental and Translational Immunology, Institute for Health Technology, Technical University of Denmark (DTU), Kongens Lyngby, Denmark
| | | | | | - Joy Nakawesi
- Immunology Section, Lund University, Lund, Sweden
| | - Katharina Lahl
- Immunology Section, Lund University, Lund, Sweden.,Section for Experimental and Translational Immunology, Institute for Health Technology, Technical University of Denmark (DTU), Kongens Lyngby, Denmark
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Yang R, Yu S, Xu T, Zhang J, Wu S. Emerging role of RNA sensors in tumor microenvironment and immunotherapy. J Hematol Oncol 2022; 15:43. [PMID: 35413927 PMCID: PMC9006576 DOI: 10.1186/s13045-022-01261-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/09/2022] [Accepted: 04/01/2022] [Indexed: 12/16/2022] Open
Abstract
RNA sensors detect foreign and endogenous RNAs to protect the host by initiating innate and adaptive immune response. In tumor microenvironment (TME), activation of RNA sensors induces tumor-inhibitory cytotoxic T lymphocyte responses and inhibits the activity of immunosuppressive cells though stimulating type I IFN signaling pathway. These characteristics allow RNA sensors to be prospective targets in tumor immunotherapy. Therefore, a comprehensive understanding of the roles of RNA sensors in TME could provide new insight into the antitumor immunotherapy. Moreover, RNA sensors could be prominent triggering targets to synergize with immunotherapies. In this review, we highlight the diverse mechanisms of RNA sensors in cancer immunity and their emerging contributions in cancer immunotherapy, including monotherapy with RNA sensor agonists, as well as combination with chemotherapy, radiotherapy, immune checkpoint blockade or cancer vaccine.
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Affiliation(s)
- Rui Yang
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Sihui Yu
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Tianhan Xu
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Jiawen Zhang
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China. .,Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
| | - Sufang Wu
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
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Teleost swim bladder, an ancient air-filled organ that elicits mucosal immune responses. Cell Discov 2022; 8:31. [PMID: 35379790 PMCID: PMC8979957 DOI: 10.1038/s41421-022-00393-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/16/2021] [Accepted: 03/08/2022] [Indexed: 11/08/2022] Open
Abstract
The air-filled organs (AOs) of vertebrates (lungs and swim bladders) have evolved unique functions (air-breathing or buoyancy control in water) to adapt to different environments. Thus far, immune responses to microbes in AOs have been described exclusively in the lungs of tetrapods. Similar to lungs, swim bladders (SBs) represent a mucosal surface, a feature that leads us to hypothesize a role for SB in immunity. In this study, we demonstrate that secretory IgT (sIgT) is the key SB immunoglobulin (Ig) responding to the viral challenge, and the only Ig involved in viral neutralization in that organ. In support of these findings, we found that the viral load of the SB from fish devoid of sIgT was much higher than that of control fish. Interestingly, similar to the lungs in mammals, the SB represents the mucosal surface in fish with the lowest content of microbiota. Moreover, sIgT is the main Ig class found coating their surface, suggesting a key role of this Ig in the homeostasis of the SB microbiota. In addition to the well-established role of SB in buoyancy control, our findings reveal a previously unrecognized function of teleost SB in adaptive mucosal immune responses upon pathogenic challenge, as well as a previously unidentified role of sIgT in antiviral defense. Overall, our findings indicate that despite the phylogenetic distance and physiological roles of teleost SB and mammalian lungs, they both have evolved analogous mucosal immune responses against microbes which likely originated independently through a process of convergent evolution.
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Chan CP, Jin DY. Cytoplasmic RNA sensors and their interplay with RNA-binding partners in innate antiviral response: theme and variations. RNA (NEW YORK, N.Y.) 2022; 28:449-477. [PMID: 35031583 PMCID: PMC8925969 DOI: 10.1261/rna.079016.121] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Indexed: 06/14/2023]
Abstract
Sensing of pathogen-associated molecular patterns including viral RNA by innate immunity represents the first line of defense against viral infection. In addition to RIG-I-like receptors and NOD-like receptors, several other RNA sensors are known to mediate innate antiviral response in the cytoplasm. Double-stranded RNA-binding protein PACT interacts with prototypic RNA sensor RIG-I to facilitate its recognition of viral RNA and induction of host interferon response, but variations of this theme are seen when the functions of RNA sensors are modulated by other RNA-binding proteins to impinge on antiviral defense, proinflammatory cytokine production and cell death programs. Their discrete and coordinated actions are crucial to protect the host from infection. In this review, we will focus on cytoplasmic RNA sensors with an emphasis on their interplay with RNA-binding partners. Classical sensors such as RIG-I will be briefly reviewed. More attention will be brought to new insights on how RNA-binding partners of RNA sensors modulate innate RNA sensing and how viruses perturb the functions of RNA-binding partners.
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Affiliation(s)
- Chi-Ping Chan
- School of Biomedical Sciences and State Key Laboratory of Liver Research, Faculty of Medicine Building, Pokfulam, Hong Kong
| | - Dong-Yan Jin
- School of Biomedical Sciences and State Key Laboratory of Liver Research, Faculty of Medicine Building, Pokfulam, Hong Kong
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Coronavirus Porcine Deltacoronavirus Upregulates MHC Class I Expression through RIG-I/IRF1-Mediated NLRC5 Induction. J Virol 2022; 96:e0015822. [PMID: 35311551 DOI: 10.1128/jvi.00158-22] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/25/2022] Open
Abstract
Major histocompatibility complex class I (MHC-I) and MHC-II molecules, mainly being responsible for the processing and presentation of intracellular or extracellular antigen, respectively, are critical for antiviral immunity. Here, we reported that porcine deltacoronavirus (PDCoV) with the zoonotic potential and potential spillover from pigs to humans, upregulated the expressions of porcine MHC-I (swine leukocyte antigen class I, SLA-I) molecules and SLA-I antigen presentation associated genes instead of porcine MHC-II (SLA-II) molecules both in primary porcine enteroids and swine testicular (ST) cells at the late stage of infection, and this finding was verified in vivo. Moreover, the induction of SLA-I molecules by PDCoV infection was mediated through enhancing the expression of NOD-like receptor (NLR) family caspase recruitment domain-containing 5 (NLRC5). Mechanistic studies demonstrated that PDCoV infection robustly elevated retinoic acid-inducible gene I (RIG-I) expression, and further initiated the downstream type I interferon beta (IFN-β) production, which led to the upregulation of NLRC5 and SLA-I genes. Likewise, interferon regulatory factor 1 (IRF1) elicited by PDCoV infection directly activated the promoter activity of NLRC5, resulting in an increased expression of NLRC5 and SLA-I upregulation. Taken together, our findings advance our understanding of how PDCoV manipulates MHC molecules, and knowledge that could help inform the development of therapies and vaccines against PDCoV. IMPORTANCE MHC-I molecules play a crucial role in antiviral immunity by presenting intracellular antigens to CD8+T lymphocytes and eliminating virus-infected cells by natural killer cells' "missing-self recognition." However, the manipulation of MHC molecules by coronaviruses remains poorly understood. Here, we demonstrated that PDCoV, a zoonotic potential coronavirus efficiently infecting cells from broad species, greatly increased the expressions of porcine MHC-I (SLA-I) molecules and MHC-I antigen presentation associated genes but not porcine MHC-II (SLA-II) molecules both in vitro and in vivo. Mechanistically, the upregulation of MHC-I molecules by PDCoV infection required the master transactivator of MHC-I, NLRC5, which was mediated not only by RIG-I-initiated type I IFN signaling pathway but also by IRF1 induced by PDCoV as it could activate NLRC5 promoter activity. These results provide significant insights into the modification of the MHC class I pathway and may provide a potential therapeutic intervention for PDCoV.
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Abstract
Intestinal microbiota, dominated by bacteria, plays an important role in the occurrence and the development of alcohol-associated liver disease (ALD), which is one of the most common liver diseases around the world. With sufficient studies focusing on the gut bacterial community, chronic alcohol consumption is now known as a key factor that alters the composition of gut bacterial community, increases intestinal permeability, causes intestinal dysfunction, induces bacterial translocation, and exacerbates the process of ALD via gut-liver axis. However, gut non-bacterial communities including fungi, viruses, and archaea, which may also participate in the disease, has received little attention relative to the gut bacterial community. This paper will systematically collect the latest literatures reporting non-bacterial communities in mammalian health and disease, and review their mechanisms in promoting the development of ALD including CLEC7A pathway, Candidalysin (a peptide toxin secreted by Candida albicans), metabolites, and other chemical substances secreted or regulated by gut commensal mycobiome, virome, and archaeome, hoping to bring novel insights on our current knowledge of ALD.
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Affiliation(s)
- Wenkang Gao
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yixin Zhu
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Jin Ye
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huikuan Chu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,CONTACT Huikuan Chu Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
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Yin L, Liu X, Hu D, Luo Y, Zhang G, Liu P. Swine Enteric Coronaviruses (PEDV, TGEV, and PDCoV) Induce Divergent Interferon-Stimulated Gene Responses and Antigen Presentation in Porcine Intestinal Enteroids. Front Immunol 2022; 12:826882. [PMID: 35126380 PMCID: PMC8810500 DOI: 10.3389/fimmu.2021.826882] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/01/2021] [Accepted: 12/27/2021] [Indexed: 02/02/2023] Open
Abstract
Swine enteric coronaviruses (SECoVs) including porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), and porcine deltacoronavirus (PDCoV), account for the majority of lethal watery diarrhea in neonatal pigs and pose significant economic and public health burdens in the world. While the three SECoVs primarily infect intestinal epithelia in vivo and cause similar clinical signs, there are evident discrepancies in their cellular tropism and pathogenicity. However, the underlying mechanisms to cause the differences remain unclear. Herein, we employed porcine enteroids that are a physiologically relevant model of the intestine to assess the host epithelial responses following infection with the three SECoVs (PEDV, TGEV, and PDCoV). Although SECoVs replicated similarly in jejunal enteroids, a parallel comparison of transcriptomics datasets uncovered that PEDV and TGEV infection induced similar transcriptional profiles and exhibited a more pronounced response with more differentially expressed genes (DEGs) in jejunal enteroids compared with PDCoV infection. Notably, TGEV and PDCoV induced high levels of type I and III IFNs and IFN-stimulated gene (ISG) responses, while PEDV displayed a delayed peak and elicited a much lesser extent of IFN responses. Furthermore, TGEV and PDCoV instead of PEDV elicited a substantial upregulation of antigen-presentation genes and T cell-recruiting chemokines in enteroids. Mechanistically, we demonstrated that IFNs treatment markedly elevated the expression of NOD-like receptor (NLR) family NLRC5 and major histocompatibility complex class I (MHC-I) molecules. Together, our results indicate unique and common viral strategies for manipulating the global IFN responses and antigen presentation utilized by SECoVs, which help us a better understanding of host-SECoVs interactions.
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Amimo JO, Raev SA, Chepngeno J, Mainga AO, Guo Y, Saif L, Vlasova AN. Rotavirus Interactions With Host Intestinal Epithelial Cells. Front Immunol 2021; 12:793841. [PMID: 35003114 PMCID: PMC8727603 DOI: 10.3389/fimmu.2021.793841] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/12/2021] [Accepted: 12/06/2021] [Indexed: 12/13/2022] Open
Abstract
Rotavirus (RV) is the foremost enteric pathogen associated with severe diarrheal illness in young children (<5years) and animals worldwide. RV primarily infects mature enterocytes in the intestinal epithelium causing villus atrophy, enhanced epithelial cell turnover and apoptosis. Intestinal epithelial cells (IECs) being the first physical barrier against RV infection employs a range of innate immune strategies to counteract RVs invasion, including mucus production, toll-like receptor signaling and cytokine/chemokine production. Conversely, RVs have evolved numerous mechanisms to escape/subvert host immunity, seizing translation machinery of the host for effective replication and transmission. RV cell entry process involve penetration through the outer mucus layer, interaction with cell surface molecules and intestinal microbiota before reaching the IECs. For successful cell attachment and entry, RVs use sialic acid, histo-blood group antigens, heat shock cognate protein 70 and cell-surface integrins as attachment factors and/or (co)-receptors. In this review, a comprehensive summary of the existing knowledge of mechanisms underlying RV-IECs interactions, including the role of gut microbiota, during RV infection is presented. Understanding these mechanisms is imperative for developing efficacious strategies to control RV infections, including development of antiviral therapies and vaccines that target specific immune system antagonists within IECs.
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Affiliation(s)
- Joshua Oluoch Amimo
- Center for Food Animal Health, Department of Animal Sciences, College of Food Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
- Department of Animal Production, Faculty of Veterinary Medicine, University of Nairobi, Nairobi, Kenya
| | - Sergei Alekseevich Raev
- Center for Food Animal Health, Department of Animal Sciences, College of Food Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
| | - Juliet Chepngeno
- Center for Food Animal Health, Department of Animal Sciences, College of Food Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
| | - Alfred Omwando Mainga
- Center for Food Animal Health, Department of Animal Sciences, College of Food Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
- Department of Public Health, Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Nairobi, Nairobi, Kenya
| | - Yusheng Guo
- Center for Food Animal Health, Department of Animal Sciences, College of Food Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
| | - Linda Saif
- Center for Food Animal Health, Department of Animal Sciences, College of Food Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
| | - Anastasia N. Vlasova
- Center for Food Animal Health, Department of Animal Sciences, College of Food Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
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Patra U, Mukhopadhyay U, Mukherjee A, Dutta S, Chawla-Sarkar M. Treading a HOSTile path: Mapping the dynamic landscape of host cell-rotavirus interactions to explore novel host-directed curative dimensions. Virulence 2021; 12:1022-1062. [PMID: 33818275 PMCID: PMC8023246 DOI: 10.1080/21505594.2021.1903198] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/21/2020] [Revised: 01/20/2021] [Accepted: 03/10/2021] [Indexed: 12/27/2022] Open
Abstract
Viruses are intracellular pathogens and are dependent on host cellular resources to carry out their cycles of perpetuation. Obtaining an integrative view of host-virus interaction is of utmost importance to understand the complex and dynamic interplay between viral components and host machineries. Besides its obvious scholarly significance, a comprehensive host-virus interaction profile also provides a platform where from host determinants of pro-viral and antiviral importance can be identified and further be subjected to therapeutic intervention. Therefore, adjunct to conventional methods of prophylactic vaccination and virus-directed antivirals, this host-targeted antiviral approach holds promising therapeutic potential. In this review, we present a comprehensive landscape of host cellular reprogramming in response to infection with rotavirus (RV) which causes profuse watery diarrhea in neonates and infants. In addition, an emphasis is given on how host determinants are either usurped or subverted by RV in course of infection and how therapeutic manipulation of specific host factors can effectively modulate the RV life cycle.
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Affiliation(s)
- Upayan Patra
- Division of Virology, National Institute of Cholera and Enteric Diseases, Beliaghata, Kolkata, India
| | - Urbi Mukhopadhyay
- Division of Virology, National Institute of Cholera and Enteric Diseases, Beliaghata, Kolkata, India
| | - Arpita Mukherjee
- Division of Virology, National Institute of Cholera and Enteric Diseases, Beliaghata, Kolkata, India
| | - Shanta Dutta
- Division of Bacteriology, National Institute of Cholera and Enteric Diseases, Beliaghata, Kolkata, India
| | - Mamta Chawla-Sarkar
- Division of Virology, National Institute of Cholera and Enteric Diseases, Beliaghata, Kolkata, India
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Bomidi C, Robertson M, Coarfa C, Estes MK, Blutt SE. Single-cell sequencing of rotavirus-infected intestinal epithelium reveals cell-type specific epithelial repair and tuft cell infection. Proc Natl Acad Sci U S A 2021; 118:e2112814118. [PMID: 34732579 PMCID: PMC8609316 DOI: 10.1073/pnas.2112814118] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Accepted: 09/14/2021] [Indexed: 12/20/2022] Open
Abstract
Intestinal epithelial damage is associated with most digestive diseases and results in detrimental effects on nutrient absorption and production of hormones and antimicrobial defense molecules. Thus, understanding epithelial repair and regeneration following damage is essential in developing therapeutics that assist in rapid healing and restoration of normal intestinal function. Here we used a well-characterized enteric virus (rotavirus) that damages the epithelium at the villus tip but does not directly damage the intestinal stem cell, to explore the regenerative transcriptional response of the intestinal epithelium at the single-cell level. We found that there are specific Lgr5+ cell subsets that exhibit increased cycling frequency associated with significant expansion of the epithelial crypt. This was accompanied by an increase in the number of immature enterocytes. Unexpectedly, we found rotavirus infects tuft cells. Transcriptional profiling indicates tuft cells respond to viral infection through interferon-related pathways. Together these data provide insights as to how the intestinal epithelium responds to insults by providing evidence of stimulation of a repair program driven by stem cells with involvement of tuft cells that results in the production of immature enterocytes that repair the damaged epithelium.
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Affiliation(s)
- Carolyn Bomidi
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030
| | - Matthew Robertson
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030
| | - Cristian Coarfa
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030
| | - Mary K Estes
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030;
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030
| | - Sarah E Blutt
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030;
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Walker FC, Sridhar PR, Baldridge MT. Differential roles of interferons in innate responses to mucosal viral infections. Trends Immunol 2021; 42:1009-1023. [PMID: 34629295 PMCID: PMC8496891 DOI: 10.1016/j.it.2021.09.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/26/2021] [Revised: 09/10/2021] [Accepted: 09/12/2021] [Indexed: 01/04/2023]
Abstract
Interferons (IFNs) are among the first vertebrate immune pathways activated upon viral infection and are crucial for control of viral replication and dissemination, especially at mucosal surfaces as key locations for host exposure to pathogens. Inhibition of viral establishment and spread at and from these mucosal sites is paramount for preventing severe disease, while concomitantly limiting putative detrimental effects of inflammation. Here, we compare the roles of type I, II, and III IFNs in regulating three archetypal viruses - norovirus, herpes simplex virus, and severe acute respiratory virus coronavirus 2 (SARS-CoV-2) - which infect distinct mammalian mucosal tissues. Emerging paradigms include highly specific roles for IFNs in limiting local versus systemic infection, synergistic activities, and a spectrum of protective versus detrimental effects of IFNs during the infection response.
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Affiliation(s)
- Forrest C Walker
- Division of Infectious Diseases, Department of Medicine, Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, USA
| | - Pratyush R Sridhar
- Division of Infectious Diseases, Department of Medicine, Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, USA
| | - Megan T Baldridge
- Division of Infectious Diseases, Department of Medicine, Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
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41
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Cananzi M, Wohler E, Marzollo A, Colavito D, You J, Jing H, Bresolin S, Gaio P, Martin R, Mescoli C, Bade S, Posey JE, Dalle Carbonare M, Tung W, Jhangiani SN, Bosa L, Zhang Y, Filho JS, Gabelli M, Kellermayer R, Kader HA, Oliva-Hemker M, Perilongo G, Lupski JR, Biffi A, Valle D, Leon A, de Macena Sobreira NL, Su HC, Guerrerio AL. IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease. Hum Genet 2021; 140:1299-1312. [PMID: 34185153 PMCID: PMC8423350 DOI: 10.1007/s00439-021-02300-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/27/2021] [Accepted: 06/07/2021] [Indexed: 02/06/2023]
Abstract
Genetic defects of innate immunity impairing intestinal bacterial sensing are linked to the development of Inflammatory Bowel Disease (IBD). Although much evidence supports a role of the intestinal virome in gut homeostasis, most studies focus on intestinal viral composition rather than on host intestinal viral sensitivity. To demonstrate the association between the development of Very Early Onset IBD (VEOIBD) and variants in the IFIH1 gene which encodes MDA5, a key cytosolic sensor for viral nucleic acids. Whole exome sequencing (WES) was performed in two independent cohorts of children with VEOIBD enrolled in Italy (n = 18) and USA (n = 24). Luciferase reporter assays were employed to assess MDA5 activity. An enrichment analysis was performed on IFIH1 comparing 42 VEOIBD probands with 1527 unrelated individuals without gastrointestinal or immunological issues. We identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD from a combined cohort of 42 children. One subject, carrying a homozygous truncating variant resulting in complete LoF, experienced neonatal-onset, pan-gastrointestinal, IBD-like enteropathy plus multiple infectious episodes. The remaining seven subjects, affected by VEOIBD without immunodeficiency, were carriers of one LoF variant in IFIH1. Among these, two patients also carried a second hypomorphic variant, with partial function apparent when MDA5 was weakly stimulated. Furthermore, IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p = 0.007). Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis.
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Affiliation(s)
- Mara Cananzi
- Unit of Pediatric Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child with Liver Transplantation, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy.
| | - Elizabeth Wohler
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Antonio Marzollo
- Pediatric Hematology, Oncology and Stem Cell Transplant Division, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
- Istituto di Ricerca Pediatrica, Fondazione Città della Speranza, Padova, Italy
| | - Davide Colavito
- Research & Innovation (R&I Genetics) Srl, C.so Stati Uniti 4, Padova, Italy
| | - Jing You
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Huie Jing
- Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Silvia Bresolin
- Pediatric Hematology, Oncology and Stem Cell Transplant Division, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
- Istituto di Ricerca Pediatrica, Fondazione Città della Speranza, Padova, Italy
| | - Paola Gaio
- Unit of Pediatric Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child with Liver Transplantation, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
| | - Renan Martin
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Claudia Mescoli
- Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University Hospital of Padova, Padova, Italy
| | - Sangeeta Bade
- Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Jennifer E Posey
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | | | - Wesley Tung
- Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Shalini N Jhangiani
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
| | - Luca Bosa
- Unit of Pediatric Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child with Liver Transplantation, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
| | - Yu Zhang
- Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Joselito Sobreira Filho
- Division of Genetics, Department of Morphology and Genetics, Universidade Federal de Sao Paulo, Sao Paulo, Brazil
| | - Maria Gabelli
- Pediatric Hematology, Oncology and Stem Cell Transplant Division, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
| | - Richard Kellermayer
- Section of Pediatric Gastroenterology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Howard A Kader
- Department of Pediatrics, Division of Pediatric Gastroenterology & Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Maria Oliva-Hemker
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Giorgio Perilongo
- Unit of Pediatric Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child with Liver Transplantation, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
| | - James R Lupski
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
- Texas Children's Hospital, Houston, Texas, USA
| | - Alessandra Biffi
- Pediatric Hematology, Oncology and Stem Cell Transplant Division, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
| | - David Valle
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Alberta Leon
- Research & Innovation (R&I Genetics) Srl, C.so Stati Uniti 4, Padova, Italy
| | | | - Helen C Su
- Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Anthony L Guerrerio
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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42
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Sarkar R, Nandi S, Lo M, Gope A, Chawla-Sarkar M. Viperin, an IFN-Stimulated Protein, Delays Rotavirus Release by Inhibiting Non-Structural Protein 4 (NSP4)-Induced Intrinsic Apoptosis. Viruses 2021; 13:1324. [PMID: 34372530 PMCID: PMC8310278 DOI: 10.3390/v13071324] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/23/2021] [Revised: 06/19/2021] [Accepted: 06/23/2021] [Indexed: 12/27/2022] Open
Abstract
Viral infections lead to expeditious activation of the host's innate immune responses, most importantly the interferon (IFN) response, which manifests a network of interferon-stimulated genes (ISGs) that constrain escalating virus replication by fashioning an ill-disposed environment. Interestingly, most viruses, including rotavirus, have evolved numerous strategies to evade or subvert host immune responses to establish successful infection. Several studies have documented the induction of ISGs during rotavirus infection. In this study, we evaluated the induction and antiviral potential of viperin, an ISG, during rotavirus infection. We observed that rotavirus infection, in a stain independent manner, resulted in progressive upregulation of viperin at increasing time points post-infection. Knockdown of viperin had no significant consequence on the production of total infectious virus particles. Interestingly, substantial escalation in progeny virus release was observed upon viperin knockdown, suggesting the antagonistic role of viperin in rotavirus release. Subsequent studies unveiled that RV-NSP4 triggered relocalization of viperin from the ER, the normal residence of viperin, to mitochondria during infection. Furthermore, mitochondrial translocation of NSP4 was found to be impeded by viperin, leading to abridged cytosolic release of Cyt c and subsequent inhibition of intrinsic apoptosis. Additionally, co-immunoprecipitation studies revealed that viperin associated with NSP4 through regions including both its radical SAM domain and its C-terminal domain. Collectively, the present study demonstrated the role of viperin in restricting rotavirus egress from infected host cells by modulating NSP4 mediated apoptosis, highlighting a novel mechanism behind viperin's antiviral action in addition to the intricacy of viperin-virus interaction.
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Affiliation(s)
| | | | | | | | - Mamta Chawla-Sarkar
- Division of Virology, National Institute of Cholera and Enteric Diseases, P-33, C.I.T. Road Scheme-XM, Beliaghata, Kolkata 700010, India; (R.S.); (S.N.); (M.L.); (A.G.)
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43
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Li Y, Handley SA, Baldridge MT. The dark side of the gut: Virome-host interactions in intestinal homeostasis and disease. J Exp Med 2021; 218:e20201044. [PMID: 33760921 PMCID: PMC8006857 DOI: 10.1084/jem.20201044] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/21/2020] [Revised: 11/23/2020] [Accepted: 11/25/2020] [Indexed: 12/19/2022] Open
Abstract
The diverse enteric viral communities that infect microbes and the animal host collectively constitute the gut virome. Although recent advances in sequencing and analysis of metaviromes have revealed the complexity of the virome and facilitated discovery of new viruses, our understanding of the enteric virome is still incomplete. Recent studies have uncovered how virome-host interactions can contribute to beneficial or detrimental outcomes for the host. Understanding the complex interactions between enteric viruses and the intestinal immune system is a prerequisite for elucidating their role in intestinal diseases. In this review, we provide an overview of the enteric virome composition and summarize recent findings about how enteric viruses are sensed by and, in turn, modulate host immune responses during homeostasis and disease.
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Affiliation(s)
- Yuhao Li
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO
- Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO
| | - Scott A. Handley
- Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO
| | - Megan T. Baldridge
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO
- Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO
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44
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Julio-Pieper M, López-Aguilera A, Eyzaguirre-Velásquez J, Olavarría-Ramírez L, Ibacache-Quiroga C, Bravo JA, Cruz G. Gut Susceptibility to Viral Invasion: Contributing Roles of Diet, Microbiota and Enteric Nervous System to Mucosal Barrier Preservation. Int J Mol Sci 2021; 22:ijms22094734. [PMID: 33946994 PMCID: PMC8125429 DOI: 10.3390/ijms22094734] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/28/2021] [Revised: 04/24/2021] [Accepted: 04/26/2021] [Indexed: 02/08/2023] Open
Abstract
The gastrointestinal lumen is a rich source of eukaryotic and prokaryotic viruses which, together with bacteria, fungi and other microorganisms comprise the gut microbiota. Pathogenic viruses inhabiting this niche have the potential to induce local as well as systemic complications; among them, the viral ability to disrupt the mucosal barrier is one mechanism associated with the promotion of diarrhea and tissue invasion. This review gathers recent evidence showing the contributing effects of diet, gut microbiota and the enteric nervous system to either support or impair the mucosal barrier in the context of viral attack.
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Affiliation(s)
- Marcela Julio-Pieper
- Grupo de NeuroGastroBioquímica, Instituto de Química, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso 2340000, Chile; (A.L.-A.); (J.E.-V.); (J.A.B.)
- Correspondence:
| | - Alejandra López-Aguilera
- Grupo de NeuroGastroBioquímica, Instituto de Química, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso 2340000, Chile; (A.L.-A.); (J.E.-V.); (J.A.B.)
| | - Johana Eyzaguirre-Velásquez
- Grupo de NeuroGastroBioquímica, Instituto de Química, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso 2340000, Chile; (A.L.-A.); (J.E.-V.); (J.A.B.)
| | | | - Claudia Ibacache-Quiroga
- Centro de Micro-Bioinnovación (CMBi), Escuela de Nutrición y Dietética, Facultad de Farmacia, Universidad de Valparaíso, Valparaíso 2340000, Chile;
| | - Javier A. Bravo
- Grupo de NeuroGastroBioquímica, Instituto de Química, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso 2340000, Chile; (A.L.-A.); (J.E.-V.); (J.A.B.)
| | - Gonzalo Cruz
- Centro de Neurobiología y Fisiopatología Integrativa (CENFI), Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2340000, Chile;
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45
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Rotavirus NSP1 Inhibits Type I and Type III Interferon Induction. Viruses 2021; 13:v13040589. [PMID: 33807175 PMCID: PMC8066714 DOI: 10.3390/v13040589] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/01/2021] [Revised: 03/26/2021] [Accepted: 03/29/2021] [Indexed: 12/24/2022] Open
Abstract
Type I interferons (IFNs) are produced by most cells in response to virus infection and stimulate a program of anti-viral gene expression in neighboring cells to suppress virus replication. Type III IFNs have similar properties, however their effects are limited to epithelial cells at mucosal surfaces due to restricted expression of the type III IFN receptor. Rotavirus (RV) replicates in intestinal epithelial cells that respond predominantly to type III IFNs, and it has been shown that type III rather than type I IFNs are important for controlling RV infections in vivo. The RV NSP1 protein antagonizes the host type I IFN response by targeting IRF-3, IRF-5, IRF-7, or β-TrCP for proteasome-mediated degradation in a strain-specific manner. Here we provide the first demonstration that NSP1 proteins from several human and animal RV strains antagonize type III as well as type I IFN induction. We also show that NSP1 is a potent inhibitor of IRF-1, a previously undescribed property of NSP1 which is conserved among human and animal RVs. Interestingly, all NSP1 proteins were substantially more effective inhibitors of IRF-1 than either IRF-3 or IRF-7 which has significance for evasion of basal anti-viral immunity and type III IFN induction in the intestinal epithelium.
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46
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Transcriptional and Non-Transcriptional Activation, Posttranslational Modifications, and Antiviral Functions of Interferon Regulatory Factor 3 and Viral Antagonism by the SARS-Coronavirus. Viruses 2021; 13:v13040575. [PMID: 33805458 PMCID: PMC8066409 DOI: 10.3390/v13040575] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/24/2021] [Revised: 03/22/2021] [Accepted: 03/24/2021] [Indexed: 12/12/2022] Open
Abstract
The immune system defends against invading pathogens through the rapid activation of innate immune signaling pathways. Interferon regulatory factor 3 (IRF3) is a key transcription factor activated in response to virus infection and is largely responsible for establishing an antiviral state in the infected host. Studies in Irf3−/− mice have demonstrated the absence of IRF3 imparts a high degree of susceptibility to a wide range of viral infections. Virus infection causes the activation of IRF3 to transcribe type-I interferon (e.g., IFNβ), which is responsible for inducing the interferon-stimulated genes (ISGs), which act at specific stages to limit virus replication. In addition to its transcriptional function, IRF3 is also activated to trigger apoptosis of virus-infected cells, as a mechanism to restrict virus spread within the host, in a pathway called RIG-I-like receptor-induced IRF3 mediated pathway of apoptosis (RIPA). These dual functions of IRF3 work in concert to mediate protective immunity against virus infection. These two pathways are activated differentially by the posttranslational modifications (PTMs) of IRF3. Moreover, PTMs regulate not only IRF3 activation and function, but also protein stability. Consequently, many viruses utilize viral proteins or hijack cellular enzymes to inhibit IRF3 functions. This review will describe the PTMs that regulate IRF3′s RIPA and transcriptional activities and use coronavirus as a model virus capable of antagonizing IRF3-mediated innate immune responses. A thorough understanding of the cellular control of IRF3 and the mechanisms that viruses use to subvert this system is critical for developing novel therapies for virus-induced pathologies.
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47
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Iliev ID, Cadwell K. Effects of Intestinal Fungi and Viruses on Immune Responses and Inflammatory Bowel Diseases. Gastroenterology 2021; 160:1050-1066. [PMID: 33347881 PMCID: PMC7956156 DOI: 10.1053/j.gastro.2020.06.100] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 04/06/2020] [Revised: 06/23/2020] [Accepted: 06/23/2020] [Indexed: 12/26/2022]
Abstract
The intestinal microbiota comprises diverse fungal and viral components, in addition to bacteria. These microbes interact with the immune system and affect human physiology. Advances in metagenomics have associated inflammatory and autoimmune diseases with alterations in fungal and viral species in the gut. Studies of animal models have found that commensal fungi and viruses can activate host-protective immune pathways related to epithelial barrier integrity, but can also induce reactions that contribute to events associated with inflammatory bowel disease. Changes in our environment associated with modernization and the COVID-19 pandemic have exposed humans to new fungi and viruses, with unknown consequences. We review the lessons learned from studies of animal viruses and fungi commonly detected in the human gut and how these might affect health and intestinal disease.
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Affiliation(s)
- Iliyan D Iliev
- Gastroenterology and Hepatology Division, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, New York; The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, New York; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, New York.
| | - Ken Cadwell
- Kimmel Center for Biology and Medicine, Skirball Institute, New York University Grossman School of Medicine, New York, New York; Department of Microbiology, New York University Grossman School of Medicine, New York, New York; Division of Gastroenterology and Hepatology, Department of Medicine, New York University Langone Health, New York, New York.
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48
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Zhou Y, Lu LF, Zhang C, Chen DD, Zhou XY, Li ZC, Jiang JY, Li S, Zhang YA. Grass carp cGASL negatively regulates interferon activation through autophagic degradation of MAVS. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 115:103876. [PMID: 32987012 DOI: 10.1016/j.dci.2020.103876] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 09/07/2020] [Revised: 09/22/2020] [Accepted: 09/22/2020] [Indexed: 06/11/2023]
Abstract
In mammals, cyclic GMP-AMP synthase (cGAS) is a crucial cytosolic DNA sensor responsible for activating the interferon (IFN) response. A cGAS-like (cGASL) gene was previously identified from grass carp Ctenopharyngodon idellus, which is evolutionarily closest to cGAS but not a true ortholog of cGAS. Here, we found that grass carp cGASL targets mitochondrial antiviral signaling protein (MAVS) for autophagic degradation to negatively regulate fish IFN response. Firstly, the transcriptional level of cellular cgasl was upregulated by poly I:C stimulation, and overexpression of cGASL significantly decreased poly I:C- and MAVS-induced promoter activities and transcriptional levels of IFN and IFN-stimulated genes (ISGs). In addition, cGASL associated with MAVS and prompted autophagic degradation of MAVS in a dose-dependent manner. Finally, overexpression of cGASL attenuated MAVS-mediated cellular antiviral response. These results collectively indicate that cGASL negatively regulates fish IFN response by triggering autophagic degradation of MAVS.
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Affiliation(s)
- Yu Zhou
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China
| | - Long-Feng Lu
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
| | - Can Zhang
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China
| | - Dan-Dan Chen
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
| | - Xiao-Yu Zhou
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; College of Fisheries and Life Science, Dalian Ocean University, Dalian, China
| | - Zhuo-Cong Li
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China
| | - Jing-Yu Jiang
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China
| | - Shun Li
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
| | - Yong-An Zhang
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, China.
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49
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Qiao Y, Zhu S, Deng S, Zou SS, Gao B, Zang G, Wu J, Jiang Y, Liu YJ, Chen J. Human Cancer Cells Sense Cytosolic Nucleic Acids Through the RIG-I-MAVS Pathway and cGAS-STING Pathway. Front Cell Dev Biol 2021; 8:606001. [PMID: 33490069 PMCID: PMC7820189 DOI: 10.3389/fcell.2020.606001] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/14/2020] [Accepted: 12/04/2020] [Indexed: 12/24/2022] Open
Abstract
Pattern recognition receptors (PRRs) are germline-encoded host sensors of the innate immune system. Some human cancer cells have been reported to express PRRs. However, nucleic acid sensors in human cancers have not been studied in detail. Therefore, we systematically analyzed the expression, molecular cascade, and functions of TLR3, RIG-I, MDA5, LGP2, cGAS, and STING in human cancer cells. TLR3, TRIF, RIG-I, MDA5, LGP2, and MAVS were expressed in 22 cell lines. The majority of cell lines responded to only RIG-I ligands 5′-ppp-dsRNA, Poly(I:C)-HMW, Poly(I:C)-LMW, and/or Poly(dA:dT), as revealed by IRF3 phosphorylation and IFN-β secretion. IFN-β secretion was inhibited by RIG-I and MAVS knockdown. cGAS and STING were co-expressed in 10 of 22 cell lines, but IFN-β secretion was not induced by STING ligands ISD, HSV60, VACV70, Poly(dG:dC), and 3′3′-cGAMP in cGAS and STING intact cell lines. Further experiments revealed that the cGAS–STING pathway was activated, as revealed by TBK1 and IRF3 phosphorylation and IFN-β and ISG mRNA expression. These results suggest that human epithelial cancer cells respond to cytosolic RNA through the RIG-I–MAVS pathway but only sense cytosolic DNA through the cGAS–STING pathway. These findings are relevant for cancer immunotherapy approaches based on targeting nucleic acid receptors.
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Affiliation(s)
- Yuan Qiao
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Shan Zhu
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Shuanglin Deng
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Shan-Shan Zou
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Bao Gao
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Guoxia Zang
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Jing Wu
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Yuxue Jiang
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Yong-Jun Liu
- Sanofi Research and Development, Cambridge, MA, United States
| | - Jingtao Chen
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.,Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
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50
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Kim AH, Hogarty MP, Harris VC, Baldridge MT. The Complex Interactions Between Rotavirus and the Gut Microbiota. Front Cell Infect Microbiol 2021; 10:586751. [PMID: 33489932 PMCID: PMC7819889 DOI: 10.3389/fcimb.2020.586751] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/24/2020] [Accepted: 11/23/2020] [Indexed: 12/24/2022] Open
Abstract
Human rotavirus (HRV) is the leading worldwide cause of acute diarrhea-related death in children under the age of five. RV infects the small intestine, an important site of colonization by the microbiota, and studies over the past decade have begun to reveal a complex set of interactions between RV and the gut microbiota. RV infection can temporarily alter the composition of the gut microbiota and probiotic administration alleviates some symptoms of infection in vivo, suggesting reciprocal effects between the virus and the gut microbiota. While development of effective RV vaccines has offered significant protection against RV-associated mortality, vaccine effectiveness in low-income countries has been limited, potentially due to regional differences in the gut microbiota. In this mini review, we briefly detail research findings to date related to HRV vaccine cohorts, studies of natural infection, explorations of RV-microbiota interactions in gnotobiotic pig models, and highlight various in vivo and in vitro models that could be used in future studies to better define how the microbiota may regulate RV infection and host antiviral immune responses.
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Affiliation(s)
- Andrew HyoungJin Kim
- Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO, United States
| | - Michael P. Hogarty
- Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO, United States
| | - Vanessa C. Harris
- Department of Medicine, Division of Infectious Diseases and Department of Global Health (AIGHD), Amsterdam University Medical Center, Academic Medical Center, Amsterdam, Netherlands
| | - Megan T. Baldridge
- Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO, United States
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