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dc.contributor.authorZhang, Y.
dc.contributor.authorLi, S.
dc.contributor.authorYang, Z.
dc.date.accessioned2019-06-05T18:28:11Z
dc.date.available2019-06-05T18:28:11Z
dc.date.issued2018
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85044960204&doi=10.1016%2fj.jcmgh.2018.01.022&partnerID=40&md5=d1659abf9bbcf309f0a2982536a14136
dc.identifier.urihttp://hdl.handle.net/10713/9384
dc.description.abstractBackground & 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. Copyright 2018 The Authorsen_US
dc.description.urihttps://dx.doi.org/10.1016/j.jcmgh.2018.01.022en_US
dc.language.isoen-USen_US
dc.publisherElsevier Incen_US
dc.relation.ispartofCellular and Molecular Gastroenterology and Hepatology
dc.subjectAutoprocessingen_US
dc.subjectC difficileen_US
dc.subjectCysteine Proteaseen_US
dc.subjectInflammationen_US
dc.subjectToxinsen_US
dc.titleCysteine Protease-Mediated Autocleavage of Clostridium difficile Toxins Regulates Their Proinflammatory Activityen_US
dc.typeArticleen_US
dc.identifier.doi10.1016/j.jcmgh.2018.01.022


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