Cargando…
Cysteine Protease-Mediated Autocleavage of Clostridium difficile Toxins Regulates Their Proinflammatory Activity
BACKGROUND & AIMS: Clostridium difficile toxin A (TcdA) and C difficile toxin toxin B (TcdB), the major virulence factors of the bacterium, cause intestinal tissue damage and inflammation. Although the 2 toxins are homologous and share a similar domain structure, TcdA is generally more inflammat...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009800/ https://www.ncbi.nlm.nih.gov/pubmed/29930981 http://dx.doi.org/10.1016/j.jcmgh.2018.01.022 |
_version_ | 1783333467754332160 |
---|---|
author | Zhang, Yongrong Li, Shan Yang, Zhiyong Shi, Lianfa Yu, Hua Salerno-Goncalves, Rosangela Saint Fleur, Ashley Feng, Hanping |
author_facet | Zhang, Yongrong Li, Shan Yang, Zhiyong Shi, Lianfa Yu, Hua Salerno-Goncalves, Rosangela Saint Fleur, Ashley Feng, Hanping |
author_sort | Zhang, Yongrong |
collection | PubMed |
description | BACKGROUND & AIMS: Clostridium difficile toxin A (TcdA) and C difficile toxin toxin B (TcdB), the major virulence factors of the bacterium, cause intestinal tissue damage and inflammation. Although the 2 toxins are homologous and share a similar domain structure, TcdA is generally more inflammatory whereas TcdB is more cytotoxic. The functional domain of the toxins that govern the proinflammatory activities of the 2 toxins is unknown. METHODS: Here, we investigated toxin domain functions that regulate the proinflammatory activity of C difficile toxins. By using a mouse ilea loop model, human tissues, and immune cells, we examined the inflammatory responses to a series of chimeric toxins or toxin mutants deficient in specific domain functions. RESULTS: Blocking autoprocessing of TcdB by mutagenesis or chemical inhibition, while reducing cytotoxicity of the toxin, significantly enhanced its proinflammatory activities in the animal model. Furthermore, a noncleavable mutant TcdB was significantly more potent than the wild-type toxin in the induction of proinflammatory cytokines in human colonic tissues and immune cells. CONCLUSIONS: In this study, we identified a novel mechanism of regulating the biological activities of C difficile toxins in that cysteine protease-mediated autoprocessing regulates toxins’ proinflammatory activities. Our findings provide new insight into the pathogenesis of C difficile infection and the design of therapeutics against the disease. |
format | Online Article Text |
id | pubmed-6009800 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-60098002018-06-21 Cysteine Protease-Mediated Autocleavage of Clostridium difficile Toxins Regulates Their Proinflammatory Activity Zhang, Yongrong Li, Shan Yang, Zhiyong Shi, Lianfa Yu, Hua Salerno-Goncalves, Rosangela Saint Fleur, Ashley Feng, Hanping Cell Mol Gastroenterol Hepatol Original Research BACKGROUND & AIMS: Clostridium difficile toxin A (TcdA) and C difficile toxin toxin B (TcdB), the major virulence factors of the bacterium, cause intestinal tissue damage and inflammation. Although the 2 toxins are homologous and share a similar domain structure, TcdA is generally more inflammatory whereas TcdB is more cytotoxic. The functional domain of the toxins that govern the proinflammatory activities of the 2 toxins is unknown. METHODS: Here, we investigated toxin domain functions that regulate the proinflammatory activity of C difficile toxins. By using a mouse ilea loop model, human tissues, and immune cells, we examined the inflammatory responses to a series of chimeric toxins or toxin mutants deficient in specific domain functions. RESULTS: Blocking autoprocessing of TcdB by mutagenesis or chemical inhibition, while reducing cytotoxicity of the toxin, significantly enhanced its proinflammatory activities in the animal model. Furthermore, a noncleavable mutant TcdB was significantly more potent than the wild-type toxin in the induction of proinflammatory cytokines in human colonic tissues and immune cells. CONCLUSIONS: In this study, we identified a novel mechanism of regulating the biological activities of C difficile toxins in that cysteine protease-mediated autoprocessing regulates toxins’ proinflammatory activities. Our findings provide new insight into the pathogenesis of C difficile infection and the design of therapeutics against the disease. Elsevier 2018-02-09 /pmc/articles/PMC6009800/ /pubmed/29930981 http://dx.doi.org/10.1016/j.jcmgh.2018.01.022 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Research Zhang, Yongrong Li, Shan Yang, Zhiyong Shi, Lianfa Yu, Hua Salerno-Goncalves, Rosangela Saint Fleur, Ashley Feng, Hanping Cysteine Protease-Mediated Autocleavage of Clostridium difficile Toxins Regulates Their Proinflammatory Activity |
title | Cysteine Protease-Mediated Autocleavage of Clostridium difficile Toxins Regulates Their Proinflammatory Activity |
title_full | Cysteine Protease-Mediated Autocleavage of Clostridium difficile Toxins Regulates Their Proinflammatory Activity |
title_fullStr | Cysteine Protease-Mediated Autocleavage of Clostridium difficile Toxins Regulates Their Proinflammatory Activity |
title_full_unstemmed | Cysteine Protease-Mediated Autocleavage of Clostridium difficile Toxins Regulates Their Proinflammatory Activity |
title_short | Cysteine Protease-Mediated Autocleavage of Clostridium difficile Toxins Regulates Their Proinflammatory Activity |
title_sort | cysteine protease-mediated autocleavage of clostridium difficile toxins regulates their proinflammatory activity |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009800/ https://www.ncbi.nlm.nih.gov/pubmed/29930981 http://dx.doi.org/10.1016/j.jcmgh.2018.01.022 |
work_keys_str_mv | AT zhangyongrong cysteineproteasemediatedautocleavageofclostridiumdifficiletoxinsregulatestheirproinflammatoryactivity AT lishan cysteineproteasemediatedautocleavageofclostridiumdifficiletoxinsregulatestheirproinflammatoryactivity AT yangzhiyong cysteineproteasemediatedautocleavageofclostridiumdifficiletoxinsregulatestheirproinflammatoryactivity AT shilianfa cysteineproteasemediatedautocleavageofclostridiumdifficiletoxinsregulatestheirproinflammatoryactivity AT yuhua cysteineproteasemediatedautocleavageofclostridiumdifficiletoxinsregulatestheirproinflammatoryactivity AT salernogoncalvesrosangela cysteineproteasemediatedautocleavageofclostridiumdifficiletoxinsregulatestheirproinflammatoryactivity AT saintfleurashley cysteineproteasemediatedautocleavageofclostridiumdifficiletoxinsregulatestheirproinflammatoryactivity AT fenghanping cysteineproteasemediatedautocleavageofclostridiumdifficiletoxinsregulatestheirproinflammatoryactivity |