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Xiao Y, Cui Y, Zhang Y, Fu W, Liu Y, Liu F. Berberine hydrochloride enhances innate immunity to protect against pathogen infection via p38 MAPK pathway. Front Immunol 2025; 16:1536143. [PMID: 40092994 PMCID: PMC11906452 DOI: 10.3389/fimmu.2025.1536143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 02/17/2025] [Indexed: 03/19/2025] Open
Abstract
The p38 MAPK pathway, an evolutionarily conserved mechanism, plays a crucial role in defending hosts against bacterial infections in both mammals and nematodes. Activating p38 MAPK signaling has been identified as a promising strategy to strengthen innate immunity and enhance resistance to pathogenic infections across various organisms.Berberine hydrochloride (BH), an isoquinoline alkaloid derived from Coptis, is known for its diverse biological activities, including anticancer, antibacterial, anti-inflammatory, lipid-lowering, and hepatoprotective effects. However, its impact on innate immunity and the associated molecular mechanisms remains unclear. In this study, we discovered that 10 μM Berberine hydrochloride enhanced resistance against both Gram-negative pathogens, such as Pseudomonas aeruginosa, Salmonella enterica and Gram-positive pathogen Listeria monocytogenes. Notably, Berberine hydrochloride improved pathogen resistance by reducing bacterial load in the intestine. Screening of classical innate immune pathways in Caenorhabditis elegans revealed that Berberine hydrochloride conferred protection against infections through the p38 MAPK pathway, specifically by activating p38/PMK-1 signaling in the intestine to bolster innate immunity. Furthermore, Berberine hydrochloride also stimulated innate immunity in mice via the p38 MAPK pathway and significantly reduced bacterial load in the lungs. These findings indicate that Berberine hydrochloride may have therapeutic potential for protecting host from infectious diseases.
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Affiliation(s)
- Yi Xiao
- Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yingwen Cui
- Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yan Zhang
- Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
| | - Wenqiao Fu
- Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yun Liu
- Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
| | - Fang Liu
- Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
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Afridi MI, Tu H. The Roles of Distinct Transcriptional Factors in the Innate Immunity of C. elegans. Cells 2025; 14:327. [PMID: 40072056 PMCID: PMC11899719 DOI: 10.3390/cells14050327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 02/06/2025] [Accepted: 02/13/2025] [Indexed: 03/14/2025] Open
Abstract
Deleterious molecules or factors produced by pathogens can hinder the normal physiological functioning of organisms. In response to these survival challenges, organisms rely on innate immune signaling as their first line of defense, which regulates immune-responsive genes and antimicrobial peptides to protect against pathogenic infections. These genes are under the control of transcription factors, which are known to regulate the transcriptional activity of genes after binding to their regulatory sequences. Previous studies have employed Caenorhabditis elegans as a host-pathogen interaction model to demonstrate the essential role of different transcription factors in the innate immunity of worms. In this review, we summarize the advances made regarding the functioning of distinct transcription factors in the innate immune response upon pathogen infection. Finally, we discuss the open questions in the field, whose resolutions have the potential to expand our understanding of the mechanisms underlying the innate immunity of organisms.
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Affiliation(s)
- Muhammad Irfan Afridi
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha 410082, China;
| | - Haijun Tu
- Shenzhen Research Institute, Hunan University, Shenzhen 518000, China
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Xiao Y, Li L, Han C, Huang T, Ren S, Wang X, Xing Q, Liu F. Chlorogenic acid inhibits Pseudomonas toxin pyocyanin and activates mitochondrial UPR to protect host against pathogen infection. Sci Rep 2025; 15:5508. [PMID: 39953205 PMCID: PMC11829045 DOI: 10.1038/s41598-025-90255-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 02/11/2025] [Indexed: 02/17/2025] Open
Abstract
Mitochondria are required for protecting host against pathogenic bacteria by activating mitochondrial unfolded protein response (UPRmt). Chlorogenic acid (CGA), a phenolic acid compound of green coffee extracts and tea has been shown to exhibit activities such as antioxidant, antibacterial, hepatoprotective, cardioprotective, anti-inflammatory, neuroprotective, anti-obesity. However, whether CGA regulates innate immunity and the underlying molecular mechanisms remain unknown. In this study, we found that CGA increased resistance to Gram-negative pathogen Pseudomonas aeruginosa PA14 in dose dependent manner. Meanwhile, CGA enhanced innate immunity in Caenorhabditis elegans by reducing intestinal bacterial burden. CGA also inhibited the proliferation of pathogenic bacteria. Importantly, CGA inhibited the production of Pseudomonas toxin pyocyanin (PYO) to protect C. elegans from P. aeruginosa PA14 infection. Furthermore, CGA activated the UPRmt and expression of antibacterial peptide genes to promote innate immunity in C. elegans via transcription factor ATFS-1(activating transcription factor associated with stress-1). Unexpectedly, CGA enhanced innate immunity independently of other known innate immune pathways. Intriguingly, CGA also protected mice from P. aeruginosa PA14 infection and activated UPRmt. Our work revealed a conserved mechanism by which CGA promoted innate immunity and boosted its therapeutic application in the treatment of pathogen infection.
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Affiliation(s)
- Yi Xiao
- Institute of Life Sciences, Zunyi Medical University, Zunyi, 563000, Guizhou, China.
- College of Basic Medicine, Zunyi Medical University, Zunyi, 563000, Guizhou, China.
| | - Linlu Li
- Institute of Life Sciences, Zunyi Medical University, Zunyi, 563000, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Chao Han
- Institute of Life Sciences, Zunyi Medical University, Zunyi, 563000, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Tingyun Huang
- Department of Pediatric, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Shuangjie Ren
- Institute of Life Sciences, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Xiaoqin Wang
- Department of Pediatric, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Qianlu Xing
- Department of Pediatric, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China.
| | - Fang Liu
- Institute of Life Sciences, Zunyi Medical University, Zunyi, 563000, Guizhou, China.
- College of Basic Medicine, Zunyi Medical University, Zunyi, 563000, Guizhou, China.
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Mengoni B, Armeli F, Schifano E, Prencipe SA, Pompa L, Sciubba F, Brasili E, Giampaoli O, Mura F, Reverberi M, Beccaccioli M, Pinto A, De Giusti M, Uccelletti D, Businaro R, Vinci G. In Vitro and In Vivo Antioxidant and Immune Stimulation Activity of Wheat Product Extracts. Nutrients 2025; 17:302. [PMID: 39861432 PMCID: PMC11767776 DOI: 10.3390/nu17020302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/13/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND/OBJECTIVES Inflammation and oxidative stress are the main pathogenetic pathways involved in the development of several chronic degenerative diseases. Our study is aimed at assessing the antioxidant and anti-inflammatory activity of hydroalcoholic extracts obtained from wheat and its derivatives. METHODS The content of total phenolic and total flavonoid compounds and antioxidant activity were carried out by ABTS and DPPH assays. The ability of wheat extracts to promote microglia polarization towards an anti-inflammatory phenotype was evaluated analyzing the increased expression of anti-inflammatory markers by real-time qPCR and immunofluorescence assays. Antioxidant activity of all the extracts was evaluated in C. elegans by analyzing ROS levels and the expression of the antioxidant enzymes GST-4 and SOD-3 by real-time qPCR and fluorescence experiments. The expression of key genes involved in the innate immune response and stress resistance pathways-daf-16, sek-1, and pmk-1-was evaluated by real-time qPCR. RESULTS Wheat extracts showed the ability to polarize microglia cells towards an anti-inflammatory phenotype, even after the addition of LPS. An antioxidant response was detected both in microglia and in Caenorhabditis elegans nematode, where the extracts also implemented an anti-stress resilience response and stimulated the innate immunity. CONCLUSIONS The present study shows that wheat seeds, flour, chaff, and pasta present anti-inflammatory as well as antioxidant activities and may be considered as prospective positive health agents for the preparation of functional foods. Moreover, the valorization of by-products from agricultural and agro-industrial activities would also have significant implications in terms of circular economy.
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Affiliation(s)
- Beatrice Mengoni
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy; (B.M.); (F.A.)
| | - Federica Armeli
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy; (B.M.); (F.A.)
- Department of Human Sciences, European University of Rome, 00163 Rome, Italy
| | - Emily Schifano
- Department of Biology and Biotechnologies “C. Darwin”, Sapienza University of Rome, 00185 Rome, Italy; (E.S.); (L.P.); (D.U.)
| | | | - Laura Pompa
- Department of Biology and Biotechnologies “C. Darwin”, Sapienza University of Rome, 00185 Rome, Italy; (E.S.); (L.P.); (D.U.)
| | - Fabio Sciubba
- Department of Environmental Biology, Sapienza University of Rome, 00185 Rome, Italy; (F.S.); (E.B.); (F.M.); (M.R.); (M.B.)
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, 00185 Rome, Italy
| | - Elisa Brasili
- Department of Environmental Biology, Sapienza University of Rome, 00185 Rome, Italy; (F.S.); (E.B.); (F.M.); (M.R.); (M.B.)
| | - Ottavia Giampaoli
- Department of Chemistry, Sapienza University of Rome, 00185 Rome, Italy;
| | - Francesco Mura
- Department of Environmental Biology, Sapienza University of Rome, 00185 Rome, Italy; (F.S.); (E.B.); (F.M.); (M.R.); (M.B.)
| | - Massimo Reverberi
- Department of Environmental Biology, Sapienza University of Rome, 00185 Rome, Italy; (F.S.); (E.B.); (F.M.); (M.R.); (M.B.)
| | - Marzia Beccaccioli
- Department of Environmental Biology, Sapienza University of Rome, 00185 Rome, Italy; (F.S.); (E.B.); (F.M.); (M.R.); (M.B.)
| | - Alessandro Pinto
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;
| | - Maria De Giusti
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy;
| | - Daniela Uccelletti
- Department of Biology and Biotechnologies “C. Darwin”, Sapienza University of Rome, 00185 Rome, Italy; (E.S.); (L.P.); (D.U.)
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, 00185 Rome, Italy
| | - Rita Businaro
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy; (B.M.); (F.A.)
| | - Giuliana Vinci
- Department of Management, Sapienza University of Rome, 00161 Rome, Italy; (S.A.P.); (G.V.)
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Patel N, Rios J, Ganguly R, Mutafoglu C, Shalash N, Gallardo K, Saleh M, Chahine J, Kopecky E, Gujral G, Shah K, Suriano C. Toll-like receptor signaling in neurons modulates C. elegans feeding behavior in a hunger state-dependent manner. Brain Behav Immun 2025; 123:1103-1113. [PMID: 39532199 DOI: 10.1016/j.bbi.2024.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 11/07/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024] Open
Abstract
Animals face the risk of encountering pathogenic microbes while foraging for resources. Assessing the risk of nutrition vs. infection can result in the behavioral regulation of immune processes. Behavioral immunity in the nematode roundworm Caenorhabditis elegans (C. elegans) is regulated, in part, by the innate immune molecule TOL-1: a homolog of vertebrate Toll-like Receptor (TLR) proteins that influences C. elegans pathogen avoidance behaviors by promoting the development of CO2-detecting chemosensory neurons. While TOL-1's role in pathogen avoidance is well established, its role in an opposing behavior - foraging - has not been examined. In addition to pathogenic bacteria, preferred food for C. elegans, such as Escherichia coli (E. coli), create significant and aversive environmental CO2 levels which may limit feeding behaviors in a tol-1 dependent manner. We have found that in addition to conferring antibacterial immunity, TOL-1 signals in neurons through the p38 MAPK PMK-1 to promote turning behavior and limit foraging when food is abundant and that the anorectic TOL-1/PMK-1 pathway is attenuated during starvation to promote foraging. These data highlight the dynamic role of a conserved innate immune cascade in neurons during both high and low hunger states and identify mechanisms underlying the neuro-immune control of feeding strategies.
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Affiliation(s)
- Neel Patel
- Department of Biology, Montclair State University, 1 Normal Avenue, Montclair, NJ 07043, United States
| | - Joseph Rios
- Department of Biology, Montclair State University, 1 Normal Avenue, Montclair, NJ 07043, United States
| | - Retwika Ganguly
- Department of Biology, Montclair State University, 1 Normal Avenue, Montclair, NJ 07043, United States
| | - Cindy Mutafoglu
- Department of Biology, Montclair State University, 1 Normal Avenue, Montclair, NJ 07043, United States
| | - Nour Shalash
- Department of Biology, Montclair State University, 1 Normal Avenue, Montclair, NJ 07043, United States
| | - Karla Gallardo
- Department of Biology, Montclair State University, 1 Normal Avenue, Montclair, NJ 07043, United States
| | - Malak Saleh
- Department of Biology, Montclair State University, 1 Normal Avenue, Montclair, NJ 07043, United States
| | - John Chahine
- Department of Biology, Montclair State University, 1 Normal Avenue, Montclair, NJ 07043, United States
| | - Emily Kopecky
- Department of Biology, Montclair State University, 1 Normal Avenue, Montclair, NJ 07043, United States
| | - Gursimran Gujral
- Department of Biology, Montclair State University, 1 Normal Avenue, Montclair, NJ 07043, United States
| | - Kamya Shah
- Department of Biology, Montclair State University, 1 Normal Avenue, Montclair, NJ 07043, United States
| | - Christos Suriano
- Department of Biology, Montclair State University, 1 Normal Avenue, Montclair, NJ 07043, United States; Sokol Institute for Pharmaceutical Life Sciences, Montclair State University, 1 Normal Avenue, Montclair, NJ 07043, United States.
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Reigada I, Kapp K, Kaudela T, García Soria M, Oksanen T, Hanski L. Tracking Chlamydia - Host interactions and antichlamydial activity in Caenorhabditis elegans. Biomed Pharmacother 2024; 177:116956. [PMID: 38901202 DOI: 10.1016/j.biopha.2024.116956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 06/02/2024] [Accepted: 06/15/2024] [Indexed: 06/22/2024] Open
Abstract
The fading efficacy of antibiotics is a growing global health concern due to its life-threatening consequences and increased healthcare costs. Non-genetic mechanisms of antimicrobial resistance, such as those employed by Chlamydia pneumoniae and Chlamydia trachomatis, complicate treatment as these bacteria can enter a non-replicative, persistent state under stress, evading antibiotics and linking to inflammatory conditions. Understanding chlamydial persistence at the molecular level is challenging, and new models for studying Chlamydia-host interactions in vivo are urgently needed. Caenorhabditis elegans offers an alternative given its immune system and numerous orthologues of human genes. This study established C. elegans as an in vivo model for chlamydial infection. Both Chlamydia species reduced the worm's lifespan, their DNA being detectable at three- and six-days post-infection. Azithromycin at its MIC (25 nM) failed to prevent the infection-induced lifespan reduction, indicating a persister phenotype. In contrast, the methanolic extract of Schisandra chinensis berries showed anti-chlamydial activity both in vitro (in THP-1 macrophages) and in vivo, significantly extending the lifespan of infected C. elegans and reducing the bacterial load. Moreover, S. chinensis increased the transcriptional activity of SKN-1 in the worms, but was unable to impact the bacterial load or lifespan in a sek-1 defective C. elegans strain. In summary, this study validated C. elegans as a chlamydial infection model and showcased S. chinensis berries' in vivo anti-chlamydial potential, possibly through SEK/SKN-1 signaling modulation.
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Affiliation(s)
- Inés Reigada
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland
| | - Karmen Kapp
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland
| | - Theresa Kaudela
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland
| | - María García Soria
- Department of Pharmacy, Faculty of Health Sciences, Universidad San Jorge (San Jorge University), Zaragoza 50830, Spain
| | - Timo Oksanen
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland
| | - Leena Hanski
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland.
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Ciccarelli EJ, Bendelstein M, Yamamoto KK, Reich H, Savage-Dunn C. BMP signaling to pharyngeal muscle in the C. elegans response to a bacterial pathogen regulates anti-microbial peptide expression and pharyngeal pumping. Mol Biol Cell 2024; 35:ar52. [PMID: 38381557 PMCID: PMC11064665 DOI: 10.1091/mbc.e23-05-0185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 02/13/2024] [Accepted: 02/16/2024] [Indexed: 02/23/2024] Open
Abstract
Host response to pathogens recruits multiple tissues in part through conserved cell signaling pathways. In Caenorhabditis elegans, the bone morphogenetic protein (BMP) like DBL-1 signaling pathway has a role in the response to infection in addition to other roles in development and postdevelopmental functions. In the regulation of body size, the DBL-1 pathway acts through cell autonomous signal activation in the epidermis (hypodermis). We have now elucidated the tissues that respond to DBL-1 signaling upon exposure to two bacterial pathogens. The receptors and Smad signal transducers for DBL-1 are expressed in pharyngeal muscle, intestine, and epidermis. We demonstrate that expression of receptor-regulated Smad (R-Smad) gene sma-3 in the pharynx is sufficient to improve the impaired survival phenotype of sma-3 mutants and that expression of sma-3 in the intestine has no effect when exposing worms to bacterial infection of the intestine. We also show that two antimicrobial peptide genes - abf-2 and cnc-2 - are regulated by DBL-1 signaling through R-Smad SMA-3 activity in the pharynx. Finally, we show that pharyngeal pumping activity is reduced in sma-3 mutants and that other pharynx-defective mutants also have reduced survival on a bacterial pathogen. Our results identify the pharynx as a tissue that responds to BMP signaling to coordinate a systemic response to bacterial pathogens.
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Affiliation(s)
- Emma Jo Ciccarelli
- Department of Biology, Queens College, CUNY, Flushing, NY 11367
- PhD Program in Biology, The Graduate Center, CUNY, New York, NY 10016
| | | | - Katerina K. Yamamoto
- Department of Biology, Queens College, CUNY, Flushing, NY 11367
- PhD Program in Biology, The Graduate Center, CUNY, New York, NY 10016
| | - Hannah Reich
- Department of Biology, Queens College, CUNY, Flushing, NY 11367
| | - Cathy Savage-Dunn
- Department of Biology, Queens College, CUNY, Flushing, NY 11367
- PhD Program in Biology, The Graduate Center, CUNY, New York, NY 10016
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Xiao Y, Hong CA, Liu F, Shi D, Zhu X, Yu C, Jiang N, Li S, Liu Y. Caffeic acid activates mitochondrial UPR to resist pathogen infection in Caenorhabditis elegans via the transcription factor ATFS-1. Infect Immun 2024; 92:e0049423. [PMID: 38294242 PMCID: PMC10929418 DOI: 10.1128/iai.00494-23] [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] [Scholar Register] [Received: 11/29/2023] [Accepted: 12/27/2023] [Indexed: 02/01/2024] Open
Abstract
Mitochondria play roles in the resistance of Caenorhabditis elegans against pathogenic bacteria by regulating mitochondrial unfolded protein response (UPRmt). Caffeic acid (CA) (3,4-dihydroxy cinnamic acid) is a major phenolic compound present in several plant species, which exhibits biological activities such as antioxidant, anti-fibrosis, anti-inflammatory, and anti-tumor properties. However, whether caffeic acid influences the innate immune response and the underlying molecular mechanisms remains unknown. In this study, we find that 20 µM caffeic acid enhances innate immunity to resist the Gram-negative pathogen Pseudomonas aeruginosa infection in C. elegans. Meanwhile, caffeic acid also inhibits the growth of pathogenic bacteria. Furthermore, caffeic acid promotes host immune response by reducing the bacterial burden in the intestine. Through genetic screening in C. elegans, we find that caffeic acid promotes innate immunity via the transcription factor ATFS-1. In addition, caffeic acid activates the UPRmt and immune response genes for innate immune response through ATFS-1. Our work suggests that caffeic acid has the potential to protect patients from pathogen infection.
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Affiliation(s)
- Yi Xiao
- Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
- Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou, China
| | - Cao-an Hong
- Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China
- Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou, China
- School of Forensic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
| | - Fang Liu
- Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
| | - Dandan Shi
- Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China
| | - Xinting Zhu
- Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
| | - Changyan Yu
- Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
- Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou, China
| | - Nian Jiang
- Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
- Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou, China
| | - Sanhua Li
- Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
- Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yun Liu
- Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
- School of Forensic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
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Xiao Y, Zhou H, Cui Y, Zhu X, Li S, Yu C, Jiang N, Liu L, Liu F. Schisandrin A enhances pathogens resistance by targeting a conserved p38 MAPK pathway. Int Immunopharmacol 2024; 128:111472. [PMID: 38176342 DOI: 10.1016/j.intimp.2023.111472] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 12/19/2023] [Accepted: 12/29/2023] [Indexed: 01/06/2024]
Abstract
Schizandrin A (SA), also known as deoxyschizandrin, is one of the most biologically active lignans isolated from the traditional Chinese medicine Fructus schisandrae chinensis. Schisandrin A has proven benefits for anti-cancer, anti-inflammation, hepatoprotection, anti-oxidation, neuroprotection, anti-diabetes. But the influence of Schisandrin A to the innate immune response and its molecular mechanisms remain obscure. In this study, we found that Schisandrin A increased resistance to not only the Gram-negative pathogens Pseudomonas aeruginosa and Salmonella enterica but also the Gram-positive pathogen Listeria monocytogenes. Meanwhile, Schisandrin A protected the animals from the infection by enhancing the tolerance to the pathogens infection rather than by reducing the bacterial burden. Through the screening of the conserved immune pathways in Caenorhabditis elegans, we found that Schisandrin A enhanced innate immunity via p38 MAPK pathway. Furthermore, Schisandrin A increased the expression of antibacterial peptide genes, such as K08D8.5, lys-2, F35E12.5, T24B8.5, and C32H11.12 by activation PMK-1/p38 MAPK. Importantly, Schisandrin A-treated mice also enhanced resistance to P. aeruginosa PA14 infection and significantly increased the levels of active PMK-1. Thus, promoted PMK-1/p38 MAPK-mediated innate immunity by Schisandrin A is conserved from worms to mammals. Our work provides a conserved mechanism by which Schisandrin A enhances innate immune response and boosts its therapeutic application in the treatment of infectious diseases.
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Affiliation(s)
- Yi Xiao
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, China; Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou 563000, China; College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, China.
| | - Hanlin Zhou
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, China; Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou 563000, China; College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Yingwen Cui
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, China; Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou 563000, China; College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Xinting Zhu
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, China; College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Sanhua Li
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, China; Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Changyan Yu
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, China; Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Nian Jiang
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, China; Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Liu Liu
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, China; College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, China.
| | - Fang Liu
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, China; College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, China.
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10
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Ciccarelli EJ, Bendelstein M, Yamamoto KK, Reich H, Savage-Dunn C. BMP signaling to pharyngeal muscle in the C. elegans response to a bacterial pathogen regulates anti-microbial peptide expression and pharyngeal pumping. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.03.06.531324. [PMID: 36945421 PMCID: PMC10028841 DOI: 10.1101/2023.03.06.531324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/11/2023]
Abstract
Host response to pathogens recruits multiple tissues in part through conserved cell signaling pathways. In C. elegans, the bone morphogenetic protein (BMP) like DBL-1 signaling pathway has a role in the response to infection in addition to other roles in development and post-developmental functions. In the regulation of body size, the DBL-1 pathway acts through cell autonomous signal activation in the epidermis (hypodermis). We have now elucidated the tissues that respond to DBL-1 signaling upon exposure to two bacterial pathogens. The receptors and Smad signal transducers for DBL-1 are expressed in pharyngeal muscle, intestine, and epidermis. We demonstrate that expression of receptor-regulated Smad (R-Smad) gene sma-3 in the pharynx is sufficient to improve the impaired survival phenotype of sma-3 mutants and that expression of sma-3 in the intestine has no effect when exposing worms to bacterial infection of the intestine. We also show that two antimicrobial peptide genes - abf-2 and cnc-2 - are regulated by DBL-1 signaling through R-Smad SMA-3 activity in the pharynx. Finally, we show that pharyngeal pumping activity is reduced in sma-3 mutants and that other pharynx-defective mutants also have reduced survival on a bacterial pathogen. Our results identify the pharynx as a tissue that responds to BMP signaling to coordinate a systemic response to bacterial pathogens.
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Affiliation(s)
- Emma Jo Ciccarelli
- Department of Biology, Queens College, CUNY, Flushing NY
- PhD Program in Biology, The Graduate Center, CUNY, New York NY
| | | | - Katerina K. Yamamoto
- Department of Biology, Queens College, CUNY, Flushing NY
- PhD Program in Biology, The Graduate Center, CUNY, New York NY
| | - Hannah Reich
- Department of Biology, Queens College, CUNY, Flushing NY
| | - Cathy Savage-Dunn
- Department of Biology, Queens College, CUNY, Flushing NY
- PhD Program in Biology, The Graduate Center, CUNY, New York NY
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11
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Xiao Y, Liu F, Wu Q, Zhu X, Yu C, Jiang N, Li S, Liu Y. Dioscin Activates Endoplasmic Reticulum Unfolded Protein Response for Defense Against Pathogenic Bacteria in Caenorhabditis elegans via IRE-1/XBP-1 Pathway. J Infect Dis 2024; 229:237-244. [PMID: 37499184 DOI: 10.1093/infdis/jiad294] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 07/26/2023] [Indexed: 07/29/2023] Open
Abstract
The unfolded protein response (UPR) is an evolutionarily conserved pathway that senses and responds to the accumulation of misfolded proteins in the endoplasmic reticulum (ER) lumen during bacterial infection. The IRE-1/XBP-1 pathway is a major branch of the UPRER that has been conserved from yeast to human. Dioscin, a steroidal saponin exhibits a broad spectrum of properties. However, whether dioscin influences the immune response and the underlying molecular mechanisms remain obscure. We find that dioscin increases resistance to Gram-negative pathogen Pseudomonas aeruginosa. Furthermore, dioscin also inhibits the growth of pathogenic bacteria. Meanwhile, dioscin enhances the resistance to pathogens by reducing bacterial burden in the intestine. Through genetic screening, we find that dioscin activates the UPRER to promote innate immunity via IRE-1/XBP-1 pathway. Intriguingly, dioscin requires the neural XBP-1 for immune response. Our findings suggest that dioscin may be a viable candidate for the treatment of infectious diseases.
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Affiliation(s)
- Yi Xiao
- Guizhou Provincial College-Based Key Laboratory for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
- Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou, China
| | - Fang Liu
- Guizhou Provincial College-Based Key Laboratory for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
| | - Qinyi Wu
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Xinting Zhu
- Guizhou Provincial College-Based Key Laboratory for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
| | - Changyan Yu
- Guizhou Provincial College-Based Key Laboratory for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
- Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou, China
| | - Nian Jiang
- Guizhou Provincial College-Based Key Laboratory for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
- Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou, China
| | - Sanhua Li
- Guizhou Provincial College-Based Key Laboratory for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
- Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yun Liu
- Guizhou Provincial College-Based Key Laboratory for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
- School of Forensic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
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12
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Balaguer F, Barrena M, Enrique M, Maicas M, Álvarez B, Tortajada M, Chenoll E, Ramón D, Martorell P. Bifidobacterium animalis subsp. lactis BPL1™ and Its Lipoteichoic Acid Modulate Longevity and Improve Age/Stress-Related Behaviors in Caenorhabditis elegans. Antioxidants (Basel) 2023; 12:2107. [PMID: 38136226 PMCID: PMC10740966 DOI: 10.3390/antiox12122107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 11/30/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
Life expectancy has increased globally in recent decades, driving interest in maintaining a healthy life that includes preservation of physical and mental abilities, particularly in elderly people. The gut microbiome becomes increasingly perturbed with aging so the use of probiotics can be a strategy for maintaining a balanced gut microbiome. A previous report showed that Bifidobacterium animalis subsp. lactis BPL1™ induces through its lipoteichoic acid (LTA) fat reduction activities via the insulin/IGF-1 signaling pathway. Here, we have delved into the mechanism of action, eliminating alternative pathways as putative mechanisms. Furthermore, we have identified that BPL1™, its heat treated form (BPL1™ HT) and its LTA prolong longevity in Caenorhabditis elegans (C. elegans) in an insulin/IGF-1-dependent mechanism, and its consumption improves the oxidative stress response, gut permeability and protection against pathogenic infections. Furthermore, positive effects on C. elegans stress-related behaviors and in the Alzheimer's Disease model were found, highlighting the potential of the strain in improving the cognitive functions and proteotoxicity in the nematode. These results indicate the pivotal role of the IGF-1 pathway in the activity of the strain and pave the way for potential applications of BPL1™, BPL1™ HT and its LTA in the field of longevity and age-related markers.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Patricia Martorell
- Archer Daniels Midland, Nutrition, Health & Wellness, Biopolis S.L. Parc Científic Universitat de València, C/Catedrático Agustín Escardino Benlloch, 9, 46980 Paterna, Spain (M.B.); (M.E.); (M.T.); (E.C.)
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13
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Liu F, Zhang H, Wang H, Zhu X, Li S, Jiang N, Yu C, Liu Y, Xiao Y. The homeodomain transcription factor CEH-37 regulates PMK-1/p38 MAPK pathway to protect against intestinal infection via the phosphatase VHP-1. Cell Mol Life Sci 2023; 80:312. [PMID: 37796333 PMCID: PMC11072455 DOI: 10.1007/s00018-023-04970-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/13/2023] [Accepted: 09/18/2023] [Indexed: 10/06/2023]
Abstract
Increasing evidence indicate that the expression of defense genes at the right place and the right time are regulated by host-defense transcription factors. However, the precise mechanisms of this regulation are not well understood. Homeodomain transcription factors, encoded by homeobox genes, play crucial role for the development of multicellular eukaryotes. In this study, we demonstrated that homeodomain transcription factor CEH-37 (known as OTX2 in mammals) was a key transcription factor for host defense in Caenorhabditis elegans. Meanwhile, CEH-37 acted in the intestine to protect C. elegans against pathogen infection. We further showed that the homeodomain transcription factor CEH-37 positively regulated PMK-1/ p38 MAPK activity to promote the intestinal immunity via suppression phosphatase VHP-1. Furthermore, we demonstrated that this function was conserved, because the human homeodomain transcription factor OTX2 also exhibited protective function in lung epithelial cells during Pseudomonas aeruginosa infection. Thus, our work reveal that CEH-37/OTX2 is a evolutionarily conserved transcription factor for defense against pathogen infection. The finding provides a model in which CEH-37 decreases VHP-1 phosphatase activity, allowing increased stimulation of PMK-1/p38 MAPK phosphorylation cascade in the intestine for pathogen resistance.
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Affiliation(s)
- Fang Liu
- Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, 563000, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Hongjiao Zhang
- Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, 563000, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, 563000, Guizhou, China
- Institute of Life Sciences, Zunyi Medical University, Zunyi , 563000, Guizhou, China
| | - Haijuan Wang
- Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, 563000, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, 563000, Guizhou, China
- Institute of Life Sciences, Zunyi Medical University, Zunyi , 563000, Guizhou, China
| | - Xinting Zhu
- Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, 563000, Guizhou, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Sanhua Li
- Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, 563000, Guizhou, China
- Institute of Life Sciences, Zunyi Medical University, Zunyi , 563000, Guizhou, China
| | - Nian Jiang
- Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, 563000, Guizhou, China
- Institute of Life Sciences, Zunyi Medical University, Zunyi , 563000, Guizhou, China
| | - Changyan Yu
- Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, 563000, Guizhou, China
- Institute of Life Sciences, Zunyi Medical University, Zunyi , 563000, Guizhou, China
| | - Yun Liu
- Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, 563000, Guizhou, China.
- College of Basic Medicine, Zunyi Medical University, Zunyi, 563000, Guizhou, China.
- Institute of Life Sciences, Zunyi Medical University, Zunyi , 563000, Guizhou, China.
| | - Yi Xiao
- Guizhou Provincial College-Based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, 563000, Guizhou, China.
- College of Basic Medicine, Zunyi Medical University, Zunyi, 563000, Guizhou, China.
- Institute of Life Sciences, Zunyi Medical University, Zunyi , 563000, Guizhou, China.
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14
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Zhang H, Zeng W, Zhao MM, Wang J, Wang Q, Chen T, Zhang Y, Lee W, Chen S, Zhang Y, Lan X, Xiang Y. Caenorhabditis elegans LIN-24, a homolog of bacterial pore-forming toxin, protects the host from microbial infection. FASEB J 2023; 37:e23162. [PMID: 37682220 DOI: 10.1096/fj.202300063r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 07/18/2023] [Accepted: 08/11/2023] [Indexed: 09/09/2023]
Abstract
Aerolysin-like pore-forming protein (af-PFP) superfamily members are double-edge swords that assist the bacterial infection but shied bacteria from the host by various mechanisms in some species including the toad Bombina maxima and zebrafish. While members of this family are widely expressed in all kingdoms, especially non-bacteria species, it remains unclear whether their anti-bacterial function is conserved. LIN-24 is an af-PFP that is constitutively expressed throughout the Caenorhabditis elegans lifespan. Here, we observed that LIN-24 knockdown reduced the maximum lifespan of worms. RNA-seq analysis identified 323 differentially expressed genes (DEGs) post-LIN-24 knockdown that were enriched in "immune response" and "lysosome pathway," suggesting a possible role for LIN-24 in resisting microbial infection. In line with this, we found that Pseudomonas aeruginosa 14 (PA14) infection induced LIN-24 expression, and that survival after PA14 infection was significantly reduced by LIN-24 knockdown. In contrast, LIN-24 overexpression (LIN-24-OE) conferred protection against PA14 infection, with worms showing longer survival time and reduced bacterial load. Weighted gene co-expression network analysis of LIN-24-OE worms showed that the highest correlation module was enriched in factors related to immunity and the defense response. Finally, by predicting transcription factors from RNA-seq data and knocking down candidate transcription factors in LIN-24-OE worms, we revealed that LIN-24 may protect worms against bacterial infection by stimulating DAF-16-mediated immune responses. These findings agree with our previous studies showing an anti-microbial role for the amphibian-derived af-PFP complex βγ-CAT, suggesting that af-PFPs may play a conserved role in combatting microbial infections. Further research is needed to determine the roles this protein family plays in other physio-pathological processes, such as metabolism, longevity, and aging.
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Affiliation(s)
- Huijie Zhang
- Metabolic Control and Aging, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, China
| | - Weirong Zeng
- Metabolic Control and Aging, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, China
| | - Ming-Ming Zhao
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, China
| | - Jiali Wang
- Metabolic Control and Aging, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, China
| | - Qiquan Wang
- Metabolic Control and Aging, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, China
| | - Ting Chen
- Metabolic Control and Aging, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, China
| | - Yuyan Zhang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, China
| | - Wenhui Lee
- Metabolic Control and Aging, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, China
| | - Shenghan Chen
- Metabolic Control and Aging, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, China
| | - Yun Zhang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, China
| | - Xinqiang Lan
- Metabolic Control and Aging, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, China
| | - Yang Xiang
- Metabolic Control and Aging, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, China
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15
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Zhuang XM, Guo ZY, Zhang M, Chen YH, Qi FN, Wang RQ, Zhang L, Zhao PJ, Lu CJ, Zou CG, Ma YC, Xu J, Zhang KQ, Cao YR, Liang LM. Ethanol mediates the interaction between Caenorhabditis elegans and the nematophagous fungus Purpureocillium lavendulum. Microbiol Spectr 2023; 11:e0127023. [PMID: 37560934 PMCID: PMC10580998 DOI: 10.1128/spectrum.01270-23] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 06/26/2023] [Indexed: 08/11/2023] Open
Abstract
Accurately recognizing pathogens by the host is vital for initiating appropriate immune response against infecting microorganisms. Caenorhabditis elegans has no known receptor to recognize pathogen-associated molecular pattern. However, recent studies showed that nematodes have a strong specificity for transcriptomes infected by different pathogens, indicating that they can identify different pathogenic microorganisms. However, the mechanism(s) for such specificity remains largely unknown. In this study, we showed that the nematophagous fungus Purpureocillium lavendulum can infect the intestinal tract of the nematode C. elegans and the infection led to the accumulation of reactive oxygen species (ROS) in the infected intestinal tract, which suppressed fungal growth. Co-transcriptional analysis revealed that fungal genes related to anaerobic respiration and ethanol production were up-regulated during infection. Meanwhile, the ethanol dehydrogenase Sodh-1 in C. elegans was also up-regulated. Together, these results suggested that the infecting fungi encounter hypoxia stress in the nematode gut and that ethanol may play a role in the host-pathogen interaction. Ethanol production in vitro during fungal cultivation in hypoxia conditions was confirmed by gas chromatography-mass spectrometry. Direct treatment of C. elegans with ethanol elevated the sodh-1 expression and ROS accumulation while repressing a series of immunity genes that were also repressed during fungal infection. Mutation of sodh-1 in C. elegans blocked ROS accumulation and increased the nematode's susceptibility to fungal infection. Our study revealed a new recognition and antifungal mechanism in C. elegans. The novel mechanism of ethanol-mediated interaction between the fungus and nematode provides new insights into fungal pathogenesis and for developing alternative biocontrol of pathogenic nematodes by nematophagous fungi. IMPORTANCE Nematodes are among the most abundant animals on our planet. Many of them are parasites in animals and plants and cause human and animal health problems as well as agricultural losses. Studying the interaction of nematodes and their microbial pathogens is of great importance for the biocontrol of animal and plant parasitic nematodes. In this study, we found that the model nematode Caenorhabditis elegans can recognize its fungal pathogen, the nematophagous fungus Purpureocillium lavendulum, through fungal-produced ethanol. Then the nematode elevated the reactive oxygen species production in the gut to inhibit fungal growth in an ethanol dehydrogenase-dependent manner. With this mechanism, novel biocontrol strategies may be developed targeting the ethanol receptor or metabolic pathway of nematodes. Meanwhile, as a volatile organic compound, ethanol should be taken seriously as a vector molecule in the microbial-host interaction in nature.
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Affiliation(s)
- Xue-Mei Zhuang
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan and The Key Laboratory for Southwest Microbial Diversity of the Ministry of Education, Yunnan University, Kunming, China
| | - Zhi-Yi Guo
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan and The Key Laboratory for Southwest Microbial Diversity of the Ministry of Education, Yunnan University, Kunming, China
| | - Meng Zhang
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan and The Key Laboratory for Southwest Microbial Diversity of the Ministry of Education, Yunnan University, Kunming, China
| | - Yong-Hong Chen
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan and The Key Laboratory for Southwest Microbial Diversity of the Ministry of Education, Yunnan University, Kunming, China
| | - Feng-Na Qi
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan and The Key Laboratory for Southwest Microbial Diversity of the Ministry of Education, Yunnan University, Kunming, China
| | - Ren-Qiao Wang
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan and The Key Laboratory for Southwest Microbial Diversity of the Ministry of Education, Yunnan University, Kunming, China
| | - Ling Zhang
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan and The Key Laboratory for Southwest Microbial Diversity of the Ministry of Education, Yunnan University, Kunming, China
| | - Pei-Ji Zhao
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan and The Key Laboratory for Southwest Microbial Diversity of the Ministry of Education, Yunnan University, Kunming, China
| | - Chao-Jun Lu
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan and The Key Laboratory for Southwest Microbial Diversity of the Ministry of Education, Yunnan University, Kunming, China
| | - Cheng-Gang Zou
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan and The Key Laboratory for Southwest Microbial Diversity of the Ministry of Education, Yunnan University, Kunming, China
| | - Yi-Cheng Ma
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan and The Key Laboratory for Southwest Microbial Diversity of the Ministry of Education, Yunnan University, Kunming, China
| | - Jianping Xu
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan and The Key Laboratory for Southwest Microbial Diversity of the Ministry of Education, Yunnan University, Kunming, China
- Department of Biology, McMaster University, Hamilton, Ontario, Canada
| | - Ke-Qin Zhang
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan and The Key Laboratory for Southwest Microbial Diversity of the Ministry of Education, Yunnan University, Kunming, China
| | - Yan-Ru Cao
- College of Agriculture and Life Sciences, Kunming University, Kunming, China
| | - Lian-Ming Liang
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan and The Key Laboratory for Southwest Microbial Diversity of the Ministry of Education, Yunnan University, Kunming, China
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16
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Khan N, Sajid M, Obaidullah AJ, Rehman W, Faris Alotaibi H, Bibi S, Alanazi MM. Nematicidal Characterization of Newly Synthesized Thiazine Derivatives Using Caenorhabditis elegans as the Model Organism. ACS OMEGA 2023; 8:20767-20778. [PMID: 37332812 PMCID: PMC10269251 DOI: 10.1021/acsomega.3c01378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 05/25/2023] [Indexed: 06/20/2023]
Abstract
In humans, animals, and agriculture, parasitic nematode infection is a very serious issue. Many drugs are being used to control nematode infections. Owing to toxicity and nematodes' resistance to the available drugs, special attention is required to synthesize new drugs that are environmentally friendly with high-level efficacy. In the present study, various substituted thiazine derivatives (1 to 15) were synthesized, and the structures were confirmed by infrared, proton (1H), and 13C NMR spectroscopies. The nematicidal potential of the synthesized derivatives was characterized using Caenorhabditis elegans (C. elegans) as a model organism. Among all synthesized compounds, 13 (LD50 = 38.95 μg/mL) and 15 (LD50 = 38.21 μg/mL) were considered the most potent compounds. Most compounds showed excellent anti-egg-hatching activity. Fluorescence microscopy confirmed that compounds 4, 8, 9, 13, and 15 displayed a high apoptotic effect. The expressions of gst-4, hsp-4, hsp16.2, and gpdh-1 genes were high in affected (treated with thiazine derivatives) C. elegans in comparison with normal C. elegans. The present research revealed that modified compounds are highly effective as they showed the gene level changes in the selected nematode. Due to structural modification in thiazine analogues, the compounds showed various modes of action. The most effective thiazine derivatives could be excellent candidates for novel broad-scale nematicidal drugs.
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Affiliation(s)
- Naqeeb
Ullah Khan
- Department
of Biochemistry, Hazara University, Mansehra, Khyber Pakhtunkhwa 21300, Pakistan
| | - Muhammad Sajid
- Department
of Biochemistry, Hazara University, Mansehra, Khyber Pakhtunkhwa 21300, Pakistan
| | - Ahmad J. Obaidullah
- Department
of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Wajid Rehman
- Department
of Chemistry, Hazara University, Mansehra, Khyber Pakhtunkhwa 21300, Pakistan
| | - Hadil Faris Alotaibi
- Department
of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia
| | - Saira Bibi
- Department
of Chemistry, Hazara University, Mansehra, Khyber Pakhtunkhwa 21300, Pakistan
| | - Mohammed M. Alanazi
- Department
of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
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17
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Xiao Y, Zhang L, Zhu X, Qin Y, Yu C, Jiang N, Li S, Liu F, Liu Y. Luteolin promotes pathogen resistance in Caenorhabditis elegans via DAF-2/DAF-16 insulin-like signaling pathway. Int Immunopharmacol 2023; 115:109679. [PMID: 36640711 DOI: 10.1016/j.intimp.2023.109679] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/20/2022] [Accepted: 12/31/2022] [Indexed: 01/15/2023]
Abstract
The DAF-2/DAF-16 insulin-like signaling pathway was an evolutionarily conserved pathway, which regulated many aspects of organismal physiology, such as pathogen resistance, metabolism, stress response, longevity. Luteolin, a flavone contained in many medical plants and in vegetables, had been shown to exhibit activities such as anti-tumor, anti-oxidant and neuroprotective effects. However, whether the Luteolin influenced the immune response and the underlying molecular mechanisms remained obscure. We found that Luteolin increased resistance to not only the Gram-negative pathogens Pseudomonas aeruginosa and Salmonella enterica but also the Gram-positive pathogens Enterococcus faecalis and Staphylococcus aureus in dose dependent manner. Meanwhile, Luteolin promoted host immune response via inhibiting the growth of pathogenic bacteria. Through the genetic screening in C. elegans, we found that Luteolin promoted innate immunity via DAF-2/DAF-16 insulin-like signaling pathway rather than p38 MAPK pathway and SKN-1. Furthermore, Luteolin activated the DAF-16/FOXO transcription factor for innate immune response. Our work suggested that Luteolin had the potential of improving the patients with pathogen infection.
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Affiliation(s)
- Yi Xiao
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, China; College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Li Zhang
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, China; College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Xinting Zhu
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, China; College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Ying Qin
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, China; College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Changyan Yu
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, China; College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Nian Jiang
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, China; College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Sanhua Li
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, China; College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Fang Liu
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, China; College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, China.
| | - Yun Liu
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou 563000, China; College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, China; Center of Forensic Expertise, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China.
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18
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Zhu X, Liu F, Wu Q, Li S, Ruan G, Yang J, Yu C, Jiang N, Xiao Y, Liu Y. Brevilin A enhances innate immunity and the resistance of oxidative stress in Caenorhabditis elegans via p38 MAPK pathway. Int Immunopharmacol 2022; 113:109385. [DOI: 10.1016/j.intimp.2022.109385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 10/09/2022] [Accepted: 10/19/2022] [Indexed: 11/05/2022]
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19
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Zhao Y, Hua X, Bian Q, Wang D. Nanoplastic Exposure at Predicted Environmental Concentrations Induces Activation of Germline Ephrin Signal Associated with Toxicity Formation in the Caenorhabditis elegans Offspring. TOXICS 2022; 10:toxics10110699. [PMID: 36422907 PMCID: PMC9696181 DOI: 10.3390/toxics10110699] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 11/15/2022] [Accepted: 11/16/2022] [Indexed: 05/04/2023]
Abstract
In nematode Caenorhabditis elegans, exposure to polystyrene nanoparticles (PS-NPs) at predicted environmental concentrations can cause induction of transgenerational toxicity. However, the underlying mechanisms for toxicity formation of PS-NP in the offspring remain largely unknown. In this study, based on high-throughput sequencing, Ephrin ligand EFN-3 was identified as a target of KSR-1/2 (two kinase suppressors of Ras) in the germline during the control of transgenerational PS-NP toxicity. At parental generation (P0-G), exposure to 0.1-10 μg/L PS-NP caused the increase in expression of germline efn-3, and this increase in germline efn-3 expression could be further detected in the offspring, such as F1-G and F2-G. Germline RNAi of efn-3 caused a resistance to transgenerational PS-NP toxicity, suggesting that the activation of germline EFN-3 at P0-G mediated transgenerational PS-NP toxicity. In the offspring, Ephrin receptor VAB-1 was further activated by the increased EFN-3 caused by PS-NP exposure at P0-G, and RNAi of vab-1 also resulted in resistance to transgenerational PS-NP toxicity. VAB-1 acted in both the neurons and the germline to control toxicity of PS-NP in the offspring. In the neurons, VAB-1 regulated PS-NP toxicity by suppressing expressions of DBL-1, JNK-1, MPK-1, and GLB-10. In the germline, VAB-1 regulated PS-NP toxicity by increasing NDK-1 and LIN-23 expressions and decreasing EGL-1 expression. Therefore, germline Ephrin ligand EFN-3 and its receptor VAB-1 acted together to mediate the formation of transgenerational PS-NP toxicity. Our data highlight the important role of activation in germline Ephrin signals in mediating transgenerational toxicity of nanoplastics at predicted environmental concentrations in organisms.
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Affiliation(s)
- Yue Zhao
- Key Laboratory of Environmental Medicine Engineering in Ministry of Education, Medical School, Southeast University, Nanjing 210009, China
- Institute of Toxicology and Risk Assessment, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210009, China
| | - Xin Hua
- Key Laboratory of Environmental Medicine Engineering in Ministry of Education, Medical School, Southeast University, Nanjing 210009, China
| | - Qian Bian
- Institute of Toxicology and Risk Assessment, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210009, China
- Correspondence: (Q.B.); (D.W.)
| | - Dayong Wang
- Key Laboratory of Environmental Medicine Engineering in Ministry of Education, Medical School, Southeast University, Nanjing 210009, China
- Shenzhen Ruipuxun Academy for Stem Cell & Regenerative Medicine, Shenzhen 518122, China
- Correspondence: (Q.B.); (D.W.)
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20
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Gauthier AE, Rotjan RD, Kagan JC. Lipopolysaccharide detection by the innate immune system may be an uncommon defence strategy used in nature. Open Biol 2022; 12:220146. [PMID: 36196535 PMCID: PMC9533005 DOI: 10.1098/rsob.220146] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 09/09/2022] [Indexed: 11/12/2022] Open
Abstract
Since the publication of the Janeway's Pattern Recognition hypothesis in 1989, study of pathogen-associated molecular patterns (PAMPs) and their immuno-stimulatory activities has accelerated. Most studies in this area have been conducted in model organisms, which leaves many open questions about the universality of PAMP biology across living systems. Mammals have evolved multiple proteins that operate as receptors for the PAMP lipopolysaccharide (LPS) from Gram-negative bacteria, but LPS is not immuno-stimulatory in all eukaryotes. In this review, we examine the history of LPS as a PAMP in mammals, recent data on LPS structure and its ability to activate mammalian innate immune receptors, and how these activities compare across commonly studied eukaryotes. We discuss why LPS may have evolved to be immuno-stimulatory in some eukaryotes but not others and propose two hypotheses about the evolution of PAMP structure based on the ecology and environmental context of the organism in question. Understanding PAMP structures and stimulatory mechanisms across multi-cellular life will provide insights into the evolutionary origins of innate immunity and may lead to the discovery of new PAMP variations of scientific and therapeutic interest.
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Affiliation(s)
- Anna E. Gauthier
- Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
- Program in Virology, Harvard Medical School, Boston, MA, USA
| | - Randi D. Rotjan
- Department of Biology, Boston University, 5 Cummington Mall, Boston, MA 02215, USA
| | - Jonathan C. Kagan
- Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
- Harvard Medical School, and Boston Children's Hospital, Division of Immunology, Division of Gastroenterology, USA
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21
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Sorrenti V, Benedetti F, Buriani A, Fortinguerra S, Caudullo G, Davinelli S, Zella D, Scapagnini G. Immunomodulatory and Antiaging Mechanisms of Resveratrol, Rapamycin, and Metformin: Focus on mTOR and AMPK Signaling Networks. Pharmaceuticals (Basel) 2022; 15:ph15080912. [PMID: 35893737 PMCID: PMC9394378 DOI: 10.3390/ph15080912] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 02/04/2023] Open
Abstract
Aging results from the progressive dysregulation of several molecular pathways and mTOR and AMPK signaling have been suggested to play a role in the complex changes in key biological networks involved in cellular senescence. Moreover, multiple factors, including poor nutritional balance, drive immunosenescence progression, one of the meaningful aspects of aging. Unsurprisingly, nutraceutical and pharmacological interventions could help maintain an optimal biological response by providing essential bioactive micronutrients required for the development, maintenance, and the expression of the immune response at all stages of life. In this regard, many studies have provided evidence of potential antiaging properties of resveratrol, as well as rapamycin and metformin. Indeed, in vitro and in vivo models have demonstrated for these molecules a number of positive effects associated with healthy aging. The current review focuses on the mechanisms of action of these three important compounds and their suggested use for the clinical treatment of immunosenescence and aging.
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Affiliation(s)
- Vincenzo Sorrenti
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Largo Egidio Meneghetti, 2, 35131 Padova, Italy
- Bendessere® Study Center, Via Prima Strada 23/3, 35129 Padova, Italy;
- Maria Paola Belloni Center for Personalized Medicine, Data Medica Group (Synlab Limited), 35100 Padova, Italy
- Correspondence: (V.S.); (D.Z.); (G.S.)
| | - Francesca Benedetti
- Department of Biochemistry and Molecular Biology, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (F.B.); (A.B.)
| | - Alessandro Buriani
- Department of Biochemistry and Molecular Biology, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (F.B.); (A.B.)
| | | | - Giada Caudullo
- Bendessere® Study Center, Via Prima Strada 23/3, 35129 Padova, Italy;
| | - Sergio Davinelli
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, Italy;
| | - Davide Zella
- Department of Biochemistry and Molecular Biology, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (F.B.); (A.B.)
- Correspondence: (V.S.); (D.Z.); (G.S.)
| | - Giovanni Scapagnini
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, Italy;
- Correspondence: (V.S.); (D.Z.); (G.S.)
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22
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Kitisin T, Muangkaew W, Sukphopetch P. Caenorhabditis elegans DAF-16 regulates lifespan and immune responses to Cryptococcus neoformans and Cryptococcus gattii infections. BMC Microbiol 2022; 22:162. [PMID: 35733100 PMCID: PMC9214972 DOI: 10.1186/s12866-022-02579-x] [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] [Scholar Register] [Received: 03/21/2022] [Accepted: 06/13/2022] [Indexed: 01/01/2023] Open
Abstract
Background Cryptococcosis is a life-threatening infection is primarily caused by two sibling species Cryptococcus neoformans and Cryptococcus gattii. Several virulence-related factors of these cryptococci have been widely investigated in Caenorhabditis elegans, representing a facile in vivo model of host–pathogen interaction. While recent studies elucidated cryptococcal virulence factors, intrinsic host factors that affect susceptibility to infections by cryptococci remain unclear and poorly investigated. Results Here, we showed that defects in C. elegans insulin/insulin-like growth factor-1 (IGF-1) signaling (IIS) pathway influenced animal lifespan and mechanisms of host resistance in cryptococcal infections, which required the activation of aging regulator DAF-16/Forkhead box O transcription factor. Moreover, accumulation of lipofuscin, DAF-16 nuclear localization, and expression of superoxide dismutase (SOD-3) were elevated in C. elegans due to host defenses during cryptococcal infections. Conclusion The present study demonstrated the relationship between longevity and immunity, which may provide a possibility for novel therapeutic intervention to improve host resistance against cryptococcal infections.
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Affiliation(s)
- Thitinan Kitisin
- Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Watcharamat Muangkaew
- Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Passanesh Sukphopetch
- Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
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23
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Wainwright CL, Teixeira MM, Adelson DL, Buenz EJ, David B, Glaser KB, Harata-Lee Y, Howes MJR, Izzo AA, Maffia P, Mayer AM, Mazars C, Newman DJ, Nic Lughadha E, Pimenta AM, Parra JA, Qu Z, Shen H, Spedding M, Wolfender JL. Future Directions for the Discovery of Natural Product-Derived Immunomodulating Drugs. Pharmacol Res 2022; 177:106076. [PMID: 35074524 DOI: 10.1016/j.phrs.2022.106076] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 01/07/2022] [Indexed: 02/06/2023]
Abstract
Drug discovery from natural sources is going through a renaissance, having spent many decades in the shadow of synthetic molecule drug discovery, despite the fact that natural product-derived compounds occupy a much greater chemical space than those created through synthetic chemistry methods. With this new era comes new possibilities, not least the novel targets that have emerged in recent times and the development of state-of-the-art technologies that can be applied to drug discovery from natural sources. Although progress has been made with some immunomodulating drugs, there remains a pressing need for new agents that can be used to treat the wide variety of conditions that arise from disruption, or over-activation, of the immune system; natural products may therefore be key in filling this gap. Recognising that, at present, there is no authoritative article that details the current state-of-the-art of the immunomodulatory activity of natural products, this in-depth review has arisen from a joint effort between the International Union of Basic and Clinical Pharmacology (IUPHAR) Natural Products and Immunopharmacology, with contributions from a Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation number of world-leading researchers in the field of natural product drug discovery, to provide a "position statement" on what natural products has to offer in the search for new immunomodulatory argents. To this end, we provide a historical look at previous discoveries of naturally occurring immunomodulators, present a picture of the current status of the field and provide insight into the future opportunities and challenges for the discovery of new drugs to treat immune-related diseases.
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Affiliation(s)
- Cherry L Wainwright
- Centre for Natural Products in Health, Robert Gordon University, Aberdeen, UK.
| | - Mauro M Teixeira
- Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Brazil.
| | - David L Adelson
- Molecular & Biomedical Science, University of Adelaide, Australia.
| | - Eric J Buenz
- Nelson Marlborough Institute of Technology, New Zealand.
| | - Bruno David
- Green Mission Pierre Fabre, Pierre Fabre Laboratories, Toulouse, France.
| | - Keith B Glaser
- AbbVie Inc., Integrated Discovery Operations, North Chicago, USA.
| | - Yuka Harata-Lee
- Molecular & Biomedical Science, University of Adelaide, Australia
| | - Melanie-Jayne R Howes
- Royal Botanic Gardens Kew, Richmond, Surrey, UK; Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, UK.
| | - Angelo A Izzo
- Department of Pharmacy, School of Medicine, University of Naples Federico II, Italy.
| | - Pasquale Maffia
- Department of Pharmacy, School of Medicine, University of Naples Federico II, Italy; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
| | - Alejandro Ms Mayer
- Department of Pharmacology, College of Graduate Studies, Midwestern University, IL, USA.
| | - Claire Mazars
- Green Mission Pierre Fabre, Pierre Fabre Laboratories, Toulouse, France.
| | | | | | - Adriano Mc Pimenta
- Laboratory of Animal Venoms and Toxins, Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
| | - John Aa Parra
- Laboratory of Animal Venoms and Toxins, Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Zhipeng Qu
- Molecular & Biomedical Science, University of Adelaide, Australia
| | - Hanyuan Shen
- Molecular & Biomedical Science, University of Adelaide, Australia
| | | | - Jean-Luc Wolfender
- School of Pharmaceutical Sciences, University of Geneva, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Switzerland.
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24
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Pujol N, Ewbank JJ. C. elegans: out on an evolutionary limb. Immunogenetics 2021; 74:63-73. [PMID: 34761293 DOI: 10.1007/s00251-021-01231-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 10/22/2021] [Indexed: 12/18/2022]
Abstract
The natural environment of the free-living nematode Caenorhabditis elegans is rich in pathogenic microbes. There is now ample evidence to indicate that these pathogens exert a strong selection pressure on C. elegans, and have shaped its genome, physiology, and behaviour. In this short review, we concentrate on how C. elegans stands out from other animals in terms of its immune repertoire and innate immune signalling pathways. We discuss how C. elegans often detects pathogens because of their effects on essential cellular processes, or organelle integrity, in addition to direct microbial recognition. We illustrate the extensive molecular plasticity that is characteristic of immune defences in C. elegans and highlight some remarkable instances of lineage-specific innovation in innate immune mechanisms.
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Affiliation(s)
- Nathalie Pujol
- Aix Marseille Univ, CNRS, INSERM, CIML, Turing Centre for Living Systems, Marseille, France.
| | - Jonathan J Ewbank
- Aix Marseille Univ, CNRS, INSERM, CIML, Turing Centre for Living Systems, Marseille, France
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25
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Probiotics Interactions and the Modulation of Major Signalling Pathways in Host Model Organism Caenorhabditis elegans. Indian J Microbiol 2021; 61:404-416. [PMID: 34744196 DOI: 10.1007/s12088-021-00961-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 06/23/2021] [Indexed: 10/21/2022] Open
Abstract
Microorganisms live in the human digestive system and the gut microbiome constitutes part of our prime determining component for healthy aging and wellness. Gut microbiota has broad influences on its host, beginning from the digestion of food and nutrients absorption to protective roles against invading pathogens and host immune system regulation. Dysbiosis of the gut microbial composition has been linked to numerous diseases and there is a need to have a better grasp on what makes a 'good' gut microbiome. Caenorhabditis elegans (C. elegans) model organism is considered as a well-suited in-vivo model system and, is at the frontline of probiotic research because of its well-defined characteristics and prolific nature. Most importantly, C. elegans feeds on bacteria, which speeds up manipulations and investigations in probiotics research tremendously. With its unique salient features of short lifespan, and ease of propagation, different unknown probiotics biological roles can be measured at an organism level with precision in the form of worm's stress responses, survivability, and lifespan. In this review, new insights on the different mechanisms underlying the establishment of probiotics regulations of conserved signalling pathways such as p38 MAPK/SKN-1, DAF-2/DAF-16, and JNK-1/DAF-16 is highlighted based on information obtained from C. elegans studies. Along with the current state of knowledge and the uniqueness of C. elegans as a model organism, explorations of its future contribution and scope in synthetic biology and probiotics engineering strains are also addressed. This is expected to strengthen our understanding of probiotics roles and to facilitate novel discovery and applications, for specific therapeutics against age-related disorders and various pathophysiological conditions.
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26
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Tsuru A, Hamazaki Y, Tomida S, Ali MS, Komura T, Nishikawa Y, Kage-Nakadai E. Nonpathogenic Cutibacterium acnes Confers Host Resistance against Staphylococcus aureus. Microbiol Spectr 2021; 9:e0056221. [PMID: 34704806 PMCID: PMC8549750 DOI: 10.1128/spectrum.00562-21] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 09/22/2021] [Indexed: 12/29/2022] Open
Abstract
Cutibacterium acnes is a human skin-resident bacterium. Although C. acnes maintains skin health by inhibiting invasion from pathogens like Staphylococcus aureus, it also contributes to several diseases, including acne. Studies suggest that differences in genetic background may explain the diverse phenotypes of C. acnes strains. In this study, we investigated the effects of C. acnes strains on the Caenorhabditis elegans life span and observed that some strains shortened the life span, whereas other strains, such as strain HL110PA4, did not alter it. Next, we assessed the effects of C. acnes HL110PA4 on host resistance against S. aureus. The survival time of C. acnes HL110PA4-fed wild-type animals was significantly longer than that of Escherichia coli OP50 control bacterium-fed worms upon infection with S. aureus. Although the survival times of worms harboring mutations at the daf-16/FoxO and skn-1/Nrf2 loci were similar to those of wild-type worms after S. aureus infection, administration of C. acnes failed to improve survival times of tir-1/SARM1, nsy-1/mitogen-activated protein kinase kinase kinase (MAPKKK), sek-1/mitogen-activated protein kinase kinase (MAPKK), and pmk-1/p38 mitogen-activated protein kinase (MAPK) mutants. These results suggest that the TIR-1 and p38 MAPK pathways are involved in conferring host resistance against S. aureus in a C. acnes-mediated manner. IMPORTANCE Cutibacterium acnes is one of the most common bacterial species residing on the human skin. Although the pathogenic properties of C. acnes, such as its association with acne vulgaris, have been widely described, its beneficial aspects have not been well characterized. Our study classifies C. acnes strains based on its pathogenic potential toward the model host C. elegans and reveals that the life span of C. elegans worms fed on C. acnes was consistent with the clinical association of C. acnes ribotypes with acne or nonacne. Furthermore, nonpathogenic C. acnes confers host resistance against the opportunistic pathogen Staphylococcus aureus. Our study provides insights into the impact of C. acnes on the host immune system and its potential roles in the ecosystem of skin microbiota.
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Affiliation(s)
- Ayano Tsuru
- Graduate School of Human Life Science, Osaka City University, Osaka, Japan
| | - Yumi Hamazaki
- Graduate School of Human Life Science, Osaka City University, Osaka, Japan
| | - Shuta Tomida
- Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan
| | | | - Tomomi Komura
- Graduate School of Human Life Science, Osaka City University, Osaka, Japan
| | - Yoshikazu Nishikawa
- Graduate School of Human Life Science, Osaka City University, Osaka, Japan
- Faculty of Human Sciences, Tezukayamagakuin University, Osaka, Japan
| | - Eriko Kage-Nakadai
- Graduate School of Human Life Science, Osaka City University, Osaka, Japan
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27
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Nguyen VTT, Meyer SC, Rieger H, Endres K. A liquid-culture-based screening approach to study compounds affecting inflammatory processes in Caenorhabditis elegans. Biol Chem 2021; 403:123-129. [PMID: 34535046 DOI: 10.1515/hsz-2021-0262] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 09/08/2021] [Indexed: 11/15/2022]
Abstract
Discovery of biomedical drugs makes use of novel biological sources of limited availability and is often in need of fast, small-scale initial screening approaches. Here, we present a screening, based on the reporter Caenorhabditis elegans strain IG692, for identification of anti- and pro-inflammatory properties. The elaborated workflow is based on cultivation in fluid and by this, allows fast and reproducible seeding in 96 well plates. LPS and dexamethasone served as reliable controls, comparable to application in the human cell line THP-1. This in vivo approach offers a first step for selection of e.g. natural products or for repurposing of compounds from drug libraries and by this can serve as a tool in drug discovery for inflammatory human diseases.
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Affiliation(s)
- Vu Thu Thuy Nguyen
- Department of Psychiatry and Psychotherapy, University Medical Centre of the Johannes Gutenberg-University Mainz, D-55131Mainz, Germany
| | - Sarah Christina Meyer
- Department of Psychiatry and Psychotherapy, University Medical Centre of the Johannes Gutenberg-University Mainz, D-55131Mainz, Germany
| | - Hanna Rieger
- Department of Psychiatry and Psychotherapy, University Medical Centre of the Johannes Gutenberg-University Mainz, D-55131Mainz, Germany
| | - Kristina Endres
- Department of Psychiatry and Psychotherapy, University Medical Centre of the Johannes Gutenberg-University Mainz, D-55131Mainz, Germany
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28
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The Drosophila Baramicin polypeptide gene protects against fungal infection. PLoS Pathog 2021; 17:e1009846. [PMID: 34432851 PMCID: PMC8423362 DOI: 10.1371/journal.ppat.1009846] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 09/07/2021] [Accepted: 07/28/2021] [Indexed: 11/19/2022] Open
Abstract
The fruit fly Drosophila melanogaster combats microbial infection by producing a battery of effector peptides that are secreted into the haemolymph. Technical difficulties prevented the investigation of these short effector genes until the recent advent of the CRISPR/CAS era. As a consequence, many putative immune effectors remain to be formally described, and exactly how each of these effectors contribute to survival is not well characterized. Here we describe a novel Drosophila antifungal peptide gene that we name Baramicin A. We show that BaraA encodes a precursor protein cleaved into multiple peptides via furin cleavage sites. BaraA is strongly immune-induced in the fat body downstream of the Toll pathway, but also exhibits expression in other tissues. Importantly, we show that flies lacking BaraA are viable but susceptible to the entomopathogenic fungus Beauveria bassiana. Consistent with BaraA being directly antimicrobial, overexpression of BaraA promotes resistance to fungi and the IM10-like peptides produced by BaraA synergistically inhibit growth of fungi in vitro when combined with a membrane-disrupting antifungal. Surprisingly, BaraA mutant males but not females display an erect wing phenotype upon infection. Here, we characterize a new antifungal immune effector downstream of Toll signalling, and show it is a key contributor to the Drosophila antimicrobial response.
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Wang Z, Zhao Y, Jiang Y, Chu W. Prebiotic, Antioxidant, and Immunomodulatory Properties of Acidic Exopolysaccharide From Marine Rhodotorula RY1801. Front Nutr 2021; 8:710668. [PMID: 34497821 PMCID: PMC8419279 DOI: 10.3389/fnut.2021.710668] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 07/23/2021] [Indexed: 12/26/2022] Open
Abstract
In this study, an extracellular acidic polysaccharide (EAPS) from marine Rhodotorula sp. RY1801 was extracted, and its biological properties were investigated. EAPS is mainly composed of monosaccharides, including mannose, rhamnose, glucose, galactose, and fucose, had an average molecular weight of 5.902 × 107 Da. The results indicated that EAPS can promote the growth of Lactobacillus acidophilus and L. acidophilus plantarum. EAPS is capable of scavenging both superoxide anion and hydroxyl radicals in vitro. The highest scavenging rate of superoxide anion and hydroxyl radicals is 29 and 84%, respectively. Using in vivo model, we found that the EAPS can expand the lifespan and increase the disease resistance of Caenorhabditis elegans against Klebsiella pneumoniae infection via the DAF-2/DAF-16 pathway. These results suggested that EAPS from marine Rhodotorula sp. RY1801 could promote the growth of beneficial bacteria and can be used as an antioxidant and immunomodulator, which had considerable potential in the food and health industry.
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Affiliation(s)
- Zheng Wang
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Yanchen Zhao
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Yan Jiang
- Animal, Plant and Food Inspection Center of Nanjing Customs, Nanjing, China
| | - Weihua Chu
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
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30
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Lukácsi S, Farkas Z, Saskői É, Bajtay Z, Takács-Vellai K. Conserved and Distinct Elements of Phagocytosis in Human and C. elegans. Int J Mol Sci 2021; 22:ijms22168934. [PMID: 34445642 PMCID: PMC8396242 DOI: 10.3390/ijms22168934] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/12/2021] [Accepted: 08/17/2021] [Indexed: 12/12/2022] Open
Abstract
Endocytosis provides the cellular nutrition and homeostasis of organisms, but pathogens often take advantage of this entry point to infect host cells. This is counteracted by phagocytosis that plays a key role in the protection against invading microbes both during the initial engulfment of pathogens and in the clearance of infected cells. Phagocytic cells balance two vital functions: preventing the accumulation of cell corpses to avoid pathological inflammation and autoimmunity, whilst maintaining host defence. In this review, we compare elements of phagocytosis in mammals and the nematode Caenorhabditis elegans. Initial recognition of infection requires different mechanisms. In mammals, pattern recognition receptors bind pathogens directly, whereas activation of the innate immune response in the nematode rather relies on the detection of cellular damage. In contrast, molecules involved in efferocytosis—the engulfment and elimination of dying cells and cell debris—are highly conserved between the two species. Therefore, C. elegans is a powerful model to research mechanisms of the phagocytic machinery. Finally, we show that both mammalian and worm studies help to understand how the two phagocytic functions are interconnected: emerging data suggest the activation of innate immunity as a consequence of defective apoptotic cell clearance.
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Affiliation(s)
- Szilvia Lukácsi
- MTA-ELTE Immunology Research Group, Eötvös Loránd Research Network (ELKH), Eötvös Loránd University, Pázmány Péter s. 1/C, 1117 Budapest, Hungary; (S.L.); (Z.B.)
| | - Zsolt Farkas
- Department of Biological Anthropology, Eötvös Loránd University, Pázmány Péter s. 1/C, 1117 Budapest, Hungary; (Z.F.); (É.S.)
| | - Éva Saskői
- Department of Biological Anthropology, Eötvös Loránd University, Pázmány Péter s. 1/C, 1117 Budapest, Hungary; (Z.F.); (É.S.)
| | - Zsuzsa Bajtay
- MTA-ELTE Immunology Research Group, Eötvös Loránd Research Network (ELKH), Eötvös Loránd University, Pázmány Péter s. 1/C, 1117 Budapest, Hungary; (S.L.); (Z.B.)
- Department of Immunology, Eötvös Loránd University, Pázmány Péter s. 1/C, 1117 Budapest, Hungary
| | - Krisztina Takács-Vellai
- Department of Biological Anthropology, Eötvös Loránd University, Pázmány Péter s. 1/C, 1117 Budapest, Hungary; (Z.F.); (É.S.)
- Correspondence:
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31
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Radeke LJ, Herman MA. Take a Walk to the Wild Side of Caenorhabditis elegans-Pathogen Interactions. Microbiol Mol Biol Rev 2021; 85:e00146-20. [PMID: 33731489 PMCID: PMC8139523 DOI: 10.1128/mmbr.00146-20] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Microbiomes form intimate functional associations with their hosts. Much has been learned from correlating changes in microbiome composition to host organismal functions. However, in-depth functional studies require the manipulation of microbiome composition coupled with the precise interrogation of organismal physiology-features available in few host study systems. Caenorhabditis elegans has proven to be an excellent genetic model organism to study innate immunity and, more recently, microbiome interactions. The study of C. elegans-pathogen interactions has provided in depth understanding of innate immune pathways, many of which are conserved in other animals. However, many bacteria were chosen for these studies because of their convenience in the lab setting or their implication in human health rather than their native interactions with C. elegans In their natural environment, C. elegans feed on a variety of bacteria found in rotting organic matter, such as rotting fruits, flowers, and stems. Recent work has begun to characterize the native microbiome and has identified a common set of bacteria found in the microbiome of C. elegans While some of these bacteria are beneficial to C. elegans health, others are detrimental, leading to a complex, multifaceted understanding of bacterium-nematode interactions. Current research on nematode-bacterium interactions is focused on these native microbiome components, both their interactions with each other and with C. elegans We will summarize our knowledge of bacterial pathogen-host interactions in C. elegans, as well as recent work on the native microbiome, and explore the incorporation of these bacterium-nematode interactions into studies of innate immunity and pathogenesis.
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Affiliation(s)
- Leah J Radeke
- School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
| | - Michael A Herman
- School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
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32
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Wibisono P, Sun J. Neuro-immune communication in C. elegans defense against pathogen infection. CURRENT RESEARCH IN IMMUNOLOGY 2021; 2:60-65. [PMID: 34368754 PMCID: PMC8344176 DOI: 10.1016/j.crimmu.2021.04.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
The innate immune system is a complex collection of physical barriers and physiological defense responses to internal and external environmental assaults. Recent studies in the model organism Caenorhabditis elegans have highlighted how the nervous system interacts with the innate immune system to generate coordinated protective responses. Indeed, studies on neuro-immune interaction pathways have provided mechanistic insights into the roles of neuro-immune communication in modulating both immune and behavioral responses to pathogen attacks. The nervous system releases a variety of neurotransmitters, peptides, and hormones that regulate the innate immune response, while the innate immune system also relays information to the nervous system to affect learning and behavioral responses. Although these interactions still need further investigation, the knowledge that we have gained thus far has improved our understanding of how separate biological systems can act collectively for the survival and well-being of an organism. Here, we review recent studies on neuro-immune communication related to the survival and defense of C. elegans against pathogens.
Neuro-immune communication is essential for generating coordinated defense against pathogen infection to improve host survival. Neuro-immune communication modulates both immune and behavioral responses to pathogen attacks. C.elegans is an excellent model system for studying neuro-immune communication.
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Affiliation(s)
- Phillip Wibisono
- Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA
| | - Jingru Sun
- Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA
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33
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Garcia-Sanchez JA, Ewbank JJ, Visvikis O. Ubiquitin-related processes and innate immunity in C. elegans. Cell Mol Life Sci 2021; 78:4305-4333. [PMID: 33630111 PMCID: PMC11072174 DOI: 10.1007/s00018-021-03787-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 01/18/2021] [Accepted: 02/03/2021] [Indexed: 02/06/2023]
Abstract
Innate immunity is an evolutionary ancient defence strategy that serves to eliminate infectious agents while maintaining host health. It involves a complex network of sensors, signaling proteins and immune effectors that detect the danger, then relay and execute the immune programme. Post-translational modifications relying on conserved ubiquitin and ubiquitin-like proteins are an integral part of the system. Studies using invertebrate models of infection, such as the nematode Caenorhabditis elegans, have greatly contributed to our understanding of how ubiquitin-related processes act in immune sensing, regulate immune signaling pathways, and participate to host defence responses. This review highlights the interest of working with a genetically tractable model organism and illustrates how C. elegans has been used to identify ubiquitin-dependent immune mechanisms, discover novel ubiquitin-based resistance strategies that mediate pathogen clearance, and unravel the role of ubiquitin-related processes in tolerance, preserving host fitness during pathogen attack. Special emphasis is placed on processes that are conserved in mammals.
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Affiliation(s)
- Juan A Garcia-Sanchez
- INSERM, C3M, Côte D'Azur University, Nice, France
- INSERM, CNRS, CIML, Turing Centre for Living Systems, Aix-Marseille University, Marseille, France
| | - Jonathan J Ewbank
- INSERM, CNRS, CIML, Turing Centre for Living Systems, Aix-Marseille University, Marseille, France.
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34
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Heat-Treated Bifidobacterium longum CECT-7347: A Whole-Cell Postbiotic with Antioxidant, Anti-Inflammatory, and Gut-Barrier Protection Properties. Antioxidants (Basel) 2021; 10:antiox10040536. [PMID: 33808122 PMCID: PMC8067082 DOI: 10.3390/antiox10040536] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/18/2021] [Accepted: 03/24/2021] [Indexed: 12/14/2022] Open
Abstract
Non-viable preparations of probiotics, as whole-cell postbiotics, attract increasing interest because of their intrinsic technological stability, and their functional properties, such as immune system modulation, gut barrier maintenance, and protection against pathogens. However, reports on Bifidobacteria-derived postbiotics remain scarce. This study aims to demonstrate the functional properties of a heat-treated (HT), non-viable, Bifidobacterium longum strain, CECT-7347, a strain previously selected for its anti-inflammatory phenotype and ability to improve biomarkers of intestinal integrity in clinical trials. The study used the nematode Caenorhabditis elegans and HT-29 cell cultures as eukaryotic model systems. Our results show that HT-CECT-7347 preserves the capacity to protect against oxidative stress damage, while it also reduces acute inflammatory response and gut-barrier disruption, and inhibits bacterial colonization, by activating pathways related to innate immune function. These findings highlight the interest of the ingredient as a novel postbiotic and pave the way to broaden the range of HT-CECT-7347 applications in gut health.
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35
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Zhou M, Liu X, Yu H, Gong J. Lactobacillus Regulates Caenorhabditis elegans Cell Signaling to Combat Salmonella Infection. Front Immunol 2021; 12:653205. [PMID: 33763087 PMCID: PMC7982399 DOI: 10.3389/fimmu.2021.653205] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 02/12/2021] [Indexed: 12/21/2022] Open
Abstract
Salmonella typhimurium DT104 infection causes the death of Caenorhabditis elegans, which can be prevented by certain Lactobacillus isolates. However, the molecular mechanisms of both the host response to the infection and the protection by Lactobacillus are largely unclear. The present study has investigated the life-span and gene expression of both wild-type (WT) and mutants in some key components of cell signaling in response to S. typhimurium infection and protection from Lactobacillus zeae. The results indicated that the gene expression of daf-16 in the DAF/ insulin-like growth factor (DAF/IGF) pathway, ced-3 and ced-9 in the programmed cell death (PCD) pathway, lys-7, spp-1, and abf-3 for antimicrobial peptide production, and bar-1 involved in the production of other defense molecules was all significantly upregulated when the wild-type (WT) was subjected to DT104 infection. On the contrary, the gene expression of tir-1, sek-1, and pmk-1 in the p38 mitogen-activated protein kinase (MAPK) pathway and clec-60, sod-3, and skn-1 for the production of other defense molecules was significantly suppressed by DT104. Pretreatment of the worms with L. zeae LB1 significantly upregulated the expression of almost all the tested genes except for ced-3, ced-9, abf-2, age-1, and dbl-1 compared with the nematode infected with DT104 only. Mutants defective in the cell signaling or other defense molecules of C. elegans were either more susceptible (defective in nsy-1, sek-1, pmk-1, ced-3, ced-9, skn-1, or daf-16) or more resistant (defective in age-1 or dbl-1) to DT104 infection than the WT except for the mutant defective in sod-3. Mutants defective in antimicrobial peptides (lys-7 or abf-3) were also more susceptible than the WT. In contrast, the mutant defective in spp-1 became more resistant. When all the mutants were pretreated with L. zeae LB1, five mutants that are defective in nsy-1, sek-1, pmk-1, abf-3, or lys-7 showed no response to the protection from LB1. These results suggest that L. zeae LB1 can regulate C. elegans cell signaling including the p38 MAPK pathway and downstream production of antimicrobial peptides and defense molecules to combat Salmonella infection.
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Affiliation(s)
- Mengzhou Zhou
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), School of Food and Biological Engineering, Hubei University of Technology, Hubei, China.,Guelph Research and Development Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada
| | - Xiaozhen Liu
- Guelph Research and Development Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada.,Engineering Research Center of Health Food Design & Nutrition Regulation, School of Chemical Engineering and Energy Technology, Dongguan University of Technology, Dongguan, China
| | - Hai Yu
- Guelph Research and Development Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada
| | - Joshua Gong
- Guelph Research and Development Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada
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36
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Xiao Y, Liu F, Li S, Jiang N, Yu C, Zhu X, Qin Y, Hui J, Meng L, Song C, Li XF, Liu Y. Metformin promotes innate immunity through a conserved PMK-1/p38 MAPK pathway. Virulence 2021; 11:39-48. [PMID: 31851866 PMCID: PMC6961722 DOI: 10.1080/21505594.2019.1706305] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Metformin, as the first-line oral drug for type 2 diabetes, has proven benefits against aging, cancer and cardiovascular diseases. But the influence of metformin to the immune response and its molecular mechanisms remain obscure. Metformin increases resistance to not only the Gram-negative pathogens Pseudomonas aeruginosa and Salmonella enterica but also the Gram-positive pathogens Enterococcus faecalis and Staphylococcus aureus. Meanwhile, metformin protects the animals from the infection by enhancing the tolerance to the pathogen infection rather than by reducing the bacterial burden. Through the screening of classical immune pathways in C. elegans, we find metformin enhances innate immunity through p38 MAPK pathway. Furthermore, activated p38/PMK-1 by metformin acts on the intestine for innate immune response. In addition, metformin-treated mice have increased resistance to P. aeruginosa PA14 infection and significantly increased the levels of active PMK-1. Therefore, promoted p38/PMK-1-mediated innate immunity by metformin is conserved from worms to mammals. Our work provides a conserved mechanism by which metformin enhances immune response and boosts its therapeutic application in the treatment of pathogen infection.
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Affiliation(s)
- Yi Xiao
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China.,Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, Guizhou, China
| | - Fang Liu
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
| | - Sanhua Li
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China.,Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, Guizhou, China
| | - Nian Jiang
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China.,Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, Guizhou, China
| | - Changyan Yu
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China.,Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, Guizhou, China
| | - Xinting Zhu
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China.,College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
| | - Ying Qin
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China.,Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, Guizhou, China
| | - Jing Hui
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China.,Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, Guizhou, China
| | - Lingjie Meng
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China.,Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, Guizhou, China
| | - Changwei Song
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China.,Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, Guizhou, China
| | - Xiao-Fei Li
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China.,College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yun Liu
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, Guizhou, China.,Research Center for Medicine & Biology, Zunyi Medical University, Zunyi, Guizhou, China
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37
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Sun L, Li H, Zhao L, Liao K. Regulation of Innate Immune Response to Fungal Infection in Caenorhabditis elegans by SHN-1/SHANK. J Microbiol Biotechnol 2020; 30:1626-1639. [PMID: 32958730 PMCID: PMC9728204 DOI: 10.4014/jmb.2006.06025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 08/14/2020] [Accepted: 09/08/2020] [Indexed: 12/15/2022]
Abstract
In Caenorhabditis elegans, SHN-1 is the homologue of SHANK, a scaffolding protein. In this study, we determined the molecular basis for SHN-1/SHANK in the regulation of innate immune response to fungal infection. Mutation of shn-1 increased the susceptibility to Candida albicans infection and suppressed the innate immune response. After C. albicans infection for 6, 12, or 24 h, both transcriptional expression of shn-1 and SHN-1::GFP expression were increased, implying that the activated SHN-1 may mediate a protection mechanism for C. elegans against the adverse effects from fungal infection. SHN-1 acted in both the neurons and the intestine to regulate the innate immune response to fungal infection. In the neurons, GLR-1, an AMPA ionotropic glutamate receptor, was identified as the downstream target in the regulation of innate immune response to fungal infection. GLR-1 further positively affected the function of SER-7-mediated serotonin signaling and antagonized the function of DAT-1-mediated dopamine signaling in the regulation of innate immune response to fungal infection. Our study suggests the novel function of SHN-1/SHANK in the regulation of innate immune response to fungal infection. Moreover, our results also denote the crucial role of neurotransmitter signals in mediating the function of SHN-1/SHANK in regulating innate immune response to fungal infection.
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Affiliation(s)
- Lingmei Sun
- Department of Pharmacology, Medical School of Southeast University, Nanjing 20009, P.R. China,Corresponding authors L.Sun Phone: +86-25-83272525 E-mail:
| | - Huirong Li
- Key Laboratory of Developmental Genes and Human Disease in Ministry of Education, Medical School, Southeast University, Nanjing 10009, P.R. China
| | - Li Zhao
- Key Laboratory of Developmental Genes and Human Disease in Ministry of Education, Medical School, Southeast University, Nanjing 10009, P.R. China
| | - Kai Liao
- Department of Pathology and Pathophysiology, Medical School of Southeast University, Nanjing 210009, P.R. China,K.Liao E-mail:
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38
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Affiliation(s)
- Brant M Webster
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
| | - Holly K Gildea
- Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA
| | - Andrew Dillin
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. .,Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA. .,Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, USA.
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39
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Natarajan O, Angeloni JT, Bilodeau MF, Russi KE, Dong Y, Cao M. The Immunomodulatory Effects of Royal Jelly on Defending Against Bacterial Infections in the Caenorhabditis elegans Model. J Med Food 2020; 24:358-369. [PMID: 32701017 DOI: 10.1089/jmf.2020.0050] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Emerging evidence suggests that aging is associated with the deterioration of immunity, a term known as immunosenescence, which may lead to a higher incidence of infections in the elderly population. Our previous studies reported that supplementation of royal jelly (RJ) extended the lifespan of Caenorhabditis elegans (C. elegans), a nematode model. The aim of this study was to investigate the potential benefits of RJ supplementation on modulation of the innate immunity in C. elegans. Using Staphylococcus aureus (S. aureus; ATCC 25923) as the infection model, we showed that RJ supplementation from the egg hatching stage could protect C. elegans against the infection. Further mechanistic studies demonstrated that RJ coordinated pathways of IIS/DAF-16, p38 MAPK, and Wnt to modulate the innate immunity. In addition, when RJ was administrated to the aged C. elegans, the worms displayed prolonged survival time to a variety of bacterial infections compared with the nontreatment group. This result indicates the RJ may help delay the innate immunosenescence.
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Affiliation(s)
- Ojas Natarajan
- Department of Biological Sciences, Clemson University, Clemson, South Carolina, USA
| | - Joseph T Angeloni
- Department of Biological Sciences, Clemson University, Clemson, South Carolina, USA
| | - Maxime F Bilodeau
- Department of Biological Sciences, Clemson University, Clemson, South Carolina, USA
| | - Kyle E Russi
- Department of Biological Sciences, Clemson University, Clemson, South Carolina, USA
| | - Yuqing Dong
- Department of Biological Sciences, Clemson University, Clemson, South Carolina, USA.,Institute for Engaged Aging, Clemson University, Clemson, South Carolina, USA
| | - Min Cao
- Department of Biological Sciences, Clemson University, Clemson, South Carolina, USA.,Institute for Engaged Aging, Clemson University, Clemson, South Carolina, USA
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40
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Zuo H, Weng K, Luo M, Yang L, Weng S, He J, Xu X. A MicroRNA-1–Mediated Inhibition of the NF-κB Pathway by the JAK-STAT Pathway in the Invertebrate Litopenaeus vannamei. THE JOURNAL OF IMMUNOLOGY 2020; 204:2918-2930. [DOI: 10.4049/jimmunol.2000071] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 03/25/2020] [Indexed: 12/20/2022]
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41
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Orihuela CJ, Maus UA, Brown JS. Can animal models really teach us anything about pneumonia? Pro. Eur Respir J 2020; 55:55/1/1901539. [DOI: 10.1183/13993003.01539-2019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 10/03/2019] [Indexed: 01/03/2023]
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42
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Caenorhabditis Elegans and Probiotics Interactions from a Prolongevity Perspective. Int J Mol Sci 2019; 20:ijms20205020. [PMID: 31658751 PMCID: PMC6834311 DOI: 10.3390/ijms20205020] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 10/09/2019] [Accepted: 10/10/2019] [Indexed: 02/08/2023] Open
Abstract
Probiotics exert beneficial effects on host health through different mechanisms of action, such as production of antimicrobial substances, competition with pathogens, enhancement of host mucosal barrier integrity and immunomodulation. In the context of ageing, which is characterized by several physiological alterations leading to a low grade inflammatory status called inflammageing, evidences suggest a potential prolongevity role of probiotics. Unraveling the mechanisms underlying anti-ageing effects requires the use of simple model systems. To this respect, the nematode Caenorhabditis elegans represents a suitable model organism for the study of both host-microbe interactions and for ageing studies, because of conserved signaling pathways and host defense mechanisms involved in the regulation of its lifespan. Therefore, this review analyses the impact of probiotics on C. elegans age-related parameters, with particular emphasis on oxidative stress, immunity, inflammation and protection from pathogen infections. The picture emerging from our analysis highlights that several probiotic strains are able to exert anti-ageing effects in nematodes by acting on common molecular pathways, such as insulin/insulin-like growth factor-1 (IIS) and p38 mitogen-activated protein kinase (p38 MAPK). In this perspective, C. elegans appears to be advantageous for shedding light on key mechanisms involved in host prolongevity in response to probiotics supplementation.
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García-Fontana C, Vílchez JI, González-Requena M, González-López J, Krell T, Matilla MA, Manzanera M. The involvement of McpB chemoreceptor from Pseudomonas aeruginosa PAO1 in virulence. Sci Rep 2019; 9:13166. [PMID: 31511598 PMCID: PMC6739360 DOI: 10.1038/s41598-019-49697-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 08/29/2019] [Indexed: 02/08/2023] Open
Abstract
Pseudomonas aeruginosa is an opportunistic human pathogen causing infections in a variety of plant and animal hosts. The gene mcpB, part of the chemosensory gene cluster II, encodes a soluble chemoreceptor whose function remains unknown. Previous studies show that the cheB2 gene, also located in the chemosensory cluster II, is involved in a specific response during infection and it is required for full pathogenicity of P. aeruginosa. To determine whether the McpB (or Aer2) chemoreceptor is involved in virulence processes, we generated a mcpB mutant and tested its phenotype using a virulence-measuring system. This system was developed by our group and is based on different bioassays using organisms living at different soil trophic levels, including microbial, nematode, arthropod, annelid, and plant model systems. The deletion of mcpB resulted in an attenuation of bacterial virulence in different infection models, and wild-type virulence was restored following genetic complementation of the mutant strain. Our study indicates that the McpB chemoreceptor is linked to virulence processes and may constitute the basis for the development of alternative strategies against this pathogen.
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Affiliation(s)
- Cristina García-Fontana
- Institute for Water Research and Department of Microbiology, University of Granada, Granada, Spain
| | - Juan I Vílchez
- Institute for Water Research and Department of Microbiology, University of Granada, Granada, Spain
| | - Marta González-Requena
- Institute for Water Research and Department of Microbiology, University of Granada, Granada, Spain
| | - Jesús González-López
- Institute for Water Research and Department of Microbiology, University of Granada, Granada, Spain
| | - Tino Krell
- Department of Environmental Protection, Estación Experimental del Zaidín, Consejo Superior de Investigaciones Científicas, Prof. Albareda 1, 18008, Granada, Spain
| | - Miguel A Matilla
- Department of Environmental Protection, Estación Experimental del Zaidín, Consejo Superior de Investigaciones Científicas, Prof. Albareda 1, 18008, Granada, Spain
| | - Maximino Manzanera
- Institute for Water Research and Department of Microbiology, University of Granada, Granada, Spain.
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White PS, Penley MJ, Tierney ARP, Soper DM, Morran LT. Dauer life stage of Caenorhabditis elegans induces elevated levels of defense against the parasite Serratia marcescens. Sci Rep 2019; 9:11575. [PMID: 31399616 PMCID: PMC6688991 DOI: 10.1038/s41598-019-47969-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 07/23/2019] [Indexed: 01/17/2023] Open
Abstract
Host-parasite research often focuses on a single host life stage, yet different life stages may exhibit different defenses. The nematode Caenorhabditis elegans has an alternate dispersal life stage, dauer. Despite dauer's importance in nature, we know little of how it responds to parasites. Previous research indicates that non-dauer C. elegans prefer to consume the virulent bacterial parasite, Serratia marcescens, when given a choice between the parasite and benign Escherichia coli. Here, we compared the preferences of dauer individuals from six strains of C. elegans to the preferences of other life stages. We found that dauer individuals exhibited reduced preference for S. marcescens, and dauers from some strains preferred E. coli to S. marcescens. In addition to testing food preference, a mechanism of parasite avoidance, we also measured host mortality rates after direct parasite exposure to determine if life stage also altered host survival. Overall, dauer individuals exhibited reduced mortality rates. However, dauer versus non-dauer larvae mortality rates also varied significantly by host strain. Collectively, we found evidence of dauer-induced parasite avoidance and reduced mortality in the presence of a parasite, but these effects were strain-specific. These results demonstrate the importance of host life stage and genotype when assessing infection dynamics.
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Affiliation(s)
- P Signe White
- Population Biology, Ecology, and Evolution Graduate Program, Emory University, Atlanta, GA, 30322, USA.
- Department of Biology, Emory University, Atlanta, GA, 30322, USA.
| | - McKenna J Penley
- Department of Biology, Emory University, Atlanta, GA, 30322, USA
| | - Aimee R Paulk Tierney
- Microbiology and Molecular Genetics Graduate Program, Emory University, Atlanta, GA, 30322, USA
| | - Deanna M Soper
- Biology Department, University of Dallas, Irving, TX, 75062, USA
| | - Levi T Morran
- Department of Biology, Emory University, Atlanta, GA, 30322, USA
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Analysis of Caenorhabditis elegans phosphoproteome reveals the involvement of a molecular chaperone, HSP-90 protein during Salmonella enterica Serovar Typhi infection. Int J Biol Macromol 2019; 137:620-646. [PMID: 31252012 DOI: 10.1016/j.ijbiomac.2019.06.085] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 06/01/2019] [Accepted: 06/12/2019] [Indexed: 02/06/2023]
Abstract
Being a primary and prerequisite Post Translational Modification (PTM), protein phosphorylation mediates the defense mechanisms that presides host defense against a pathogen attack. Hence, the current study was intended to uncover the role of regulatory proteins and their PTMs with special attention to phosphorylation during pathogen attack, using C. elegans as a host and S. Typhi as an interacting pathogen. The study was initiated with the identification of differential regulation of the crucial immune regulatory kinases such as PMK-1, JNK-1 and SGK-1 through immunoblotting analysis, which revealed up-regulation of kinases during 48 h of S. Typhi infection. Subsequent the phosphoproteome profiling of S. Typhi infected C. elegans, using TiO2 Column Chromatography followed by MALDI-ToF-ToF-MS, uncovered the regulated phosphoprotein players resulting in the identification of 166 and 54 proteins from gel-free and gel-based analysis, respectively. HSP-90 was found to be a central player from the interactome analyses and its role during pathogenic defense was validated using immunoblotting. Furthermore, the protein disorders of the identified phosphoproteins have been extensively analysed in silico. This study suggests that S. Typhi interferes with the homeostasis of chaperone molecules by kinetically interfering with the phosphorylation of the downstream pathway players of MAPK and JNK.
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Zhou M, Liu X, Yu H, Yin X, Nie SP, Xie MY, Chen W, Gong J. Cell Signaling of Caenorhabditis elegans in Response to Enterotoxigenic Escherichia coli Infection and Lactobacillus zeae Protection. Front Immunol 2018; 9:1745. [PMID: 30250464 PMCID: PMC6139356 DOI: 10.3389/fimmu.2018.01745] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 07/16/2018] [Indexed: 11/13/2022] Open
Abstract
Enterotoxigenic Escherichia coli (ETEC) infection causes the death of Caenorhabditis elegans, which can be prevented by certain Lactobacillus isolates. The host response of C. elegans to ETEC infection and its regulation by the isolates are, however, largely unclear. This study has revealed that, in agreement with the results of life-span assays, the expression of the genes encoding p38 mitogen-activated protein kinase (MAPK) pathway (nsy-1, sek-1, and pmk-1), insulin/insulin-like growth factor (DAF/IGF) pathway (daf-16), or antimicrobial peptides (lys-7, spp-1, and abf-3) and other defensing molecules (abf-2, clec-85) was upregulated significantly when the wild-type nematode (N2) was subjected to ETEC infection. This upregulation was further enhanced by the pretreatment with Lactobacillus zeae LB1, but not with L. casei CL11. Mutants defective in the cell signaling of C. elegans were either more susceptible (defective in NSY-1, SEK-1, PMK-1, or DAF16) or more resistant (defective in AGE-1, DBL-1, SKN-1, or SOD-3) to ETEC infection compared with the wild-type. Mutants defective in antimicrobial peptides (LYS-7, SPP1, or ABF-3) were also more susceptible. In addition, mutants that are defective in NSY-1, SEK-1, PMK-1, DAF16, ABF-3, LYS-7, or SPP1 showed no response to the protection from L. zeae LB1. The expression of the genes encoding antimicrobial peptides (lys-7, spp-1, and abf-3) and other defensing molecules (abf-2, clec-60, and clec-85) were almost all upregulated in AGE-1- or DBL-1-defective mutant compared with the wild-type, which was further enhanced by the pretreatment of L. zeae LB1. The expression of these genes was, however, mostly downregulated in NSY-1- or DAF-16-defective mutant. These results suggest that L. zeae LB1 regulates C. elegans signaling through the p38 MAPK and DAF/IGF pathways to control the production of antimicrobial peptides and defensing molecules to combat ETEC infection.
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Affiliation(s)
- Mengzhou Zhou
- School of Food and Biological Engineering, Hubei University of Technology, Wuhan, China.,Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada.,State Key Laboratory of Food Science and Technology/International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, China
| | - Xiaozhen Liu
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada.,State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
| | - Hai Yu
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada
| | - Xianhua Yin
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada
| | - Shao-Ping Nie
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
| | - Ming-Yong Xie
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
| | - Wei Chen
- State Key Laboratory of Food Science and Technology/International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, China
| | - Joshua Gong
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada
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Real-time monitoring of immune responses under pathogen invasion and drug interference by integrated microfluidic device coupled with worm-based biosensor. Biosens Bioelectron 2018; 110:233-238. [DOI: 10.1016/j.bios.2018.03.058] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 03/09/2018] [Accepted: 03/27/2018] [Indexed: 01/17/2023]
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GIBSON AMANDAK, MORRAN LEVIT. A Model for Evolutionary Ecology of Disease: The Case for Caenorhabditis Nematodes and Their Natural Parasites. J Nematol 2018. [DOI: 10.21307/jofnem-2017-083] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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Shu C, Sun L, Zhang W. Thymol has antifungal activity against Candida albicans during infection and maintains the innate immune response required for function of the p38 MAPK signaling pathway in Caenorhabditis elegans. Immunol Res 2017; 64:1013-24. [PMID: 26783030 DOI: 10.1007/s12026-016-8785-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The Caenorhabditis elegans model can be used to study Candida albicans virulence and host immunity, as well as to identify plant-derived natural products to use against C. albicans. Thymol is a hydrophobic phenol compound from the aromatic plant thyme. In this study, the in vitro data demonstrated concentration-dependent thymol inhibition of both C. albicans growth and biofilm formation during different developmental phases. With the aid of the C. elegans system, we performed in vivo assays, and our results further showed the ability of thymol to increase C. elegans life span during infection, inhibit C. albicans colony formation in the C. elegans intestine, and increase the expression levels of host antimicrobial genes. Moreover, among the genes that encode the p38 MAPK signaling pathway, mutation of the pmk-1 or sek-1 gene decreased the beneficial effects of thymol's antifungal activity against C. albicans and thymol's maintenance of the innate immune response in nematodes. Western blot data showed the level of phosphorylation of pmk-1 was dramatically decreased against C. albicans. In nematodes, treatment with thymol recovered the dysregulation of pmk-1 and sek-1 gene expressions, the phosphorylation level of PMK-1 caused by C. albicans infection. Therefore, thymol may act, at least in part, through the function of the p38 MAPK signaling pathway to protect against C. albicans infection and maintain the host innate immune response to C. albicans. Our results indicate that the p38 MAPK signaling pathway plays a crucial role in regulating the beneficial effects observed after nematodes infected with C. albicans were treated with thymol.
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Affiliation(s)
- Chengjie Shu
- College of Life Sciences, Nanjing Normal University, Nanjing, 210032, China.,Institute for Comprehensive Utilization of Wild Plants, Nanjing, 210042, China
| | - Lingmei Sun
- Key Laboratory of Developmental Genes and Human Disease in Ministry of Education, Medical School of Southeast University, Nanjing, 210009, China
| | - Weiming Zhang
- College of Life Sciences, Nanjing Normal University, Nanjing, 210032, China. .,Institute for Comprehensive Utilization of Wild Plants, Nanjing, 210042, China.
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Kwon G, Lee J, Koh JH, Lim YH. Lifespan Extension of Caenorhabditis elegans by Butyricicoccus pullicaecorum and Megasphaera elsdenii with Probiotic Potential. Curr Microbiol 2017; 75:557-564. [PMID: 29222621 DOI: 10.1007/s00284-017-1416-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 12/06/2017] [Indexed: 11/27/2022]
Abstract
Butyricicoccus pullicaecorum and Megasphaera elsdenii inhabit the human intestine and have probiotic potential. The aim of this study was to evaluate the effects of B. pullicaecorum and M. elsdenii on the lifespan of Caenorhabditis elegans. They significantly (P < 0.05) extended the lifespan of C. elegans compared with Escherichia coli OP50, a standard food for the worm. Analysis of age-related biomarkers such as lipofuscin, body size, and locomotory activity showed that they retarded aging. They all failed to extend the lifespan of daf-12 or dbl-1 loss-of-function C. elegans mutants compared with E. coli OP50-fed worms. However, the increase in lifespan was observed in daf-16, jnk-1, pmk-1, and skn-1 mutants. Moreover, they increased the resistance of C. elegans to a human pathogen, Salmonella typhimurium. In conclusion, B. pullicaecorum and M. elsdenii extend the lifespan of C. elegans via the transforming growth factor-beta (TGF-β) pathway associated with anti-inflammatory processes in the innate immune system.
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Affiliation(s)
- Gayeung Kwon
- Department of Public Health Science (Brain Korea 21 PLUS Program), Graduate School, Korea University, Seoul, 136-701, Republic of Korea
| | - Jiyun Lee
- Department of Public Health Science (Brain Korea 21 PLUS Program), Graduate School, Korea University, Seoul, 136-701, Republic of Korea
| | - Jong-Ho Koh
- Department of Bio-Food Analysis and Processing, Bio-Campus Korea Polytechnic College, Nonsan, Chungnam, 32943, Republic of Korea
| | - Young-Hee Lim
- Department of Public Health Science (Brain Korea 21 PLUS Program), Graduate School, Korea University, Seoul, 136-701, Republic of Korea.
- School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, 136-701, Republic of Korea.
- Department of Laboratory Medicine, Guro Hospital, Korea University, Seoul, 152-703, Republic of Korea.
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