Glucosyltransferase-dependent and independent effects of Clostridioides difficile toxins during infection

Koehler, Theresa M., Peritore-Galve, F. Christopher, Shupe, John A., Cave, Rory J., Childress, Kevin O., Washington, M. Kay, Kuehne, Sarah A. and Lacy, D. Borden (2022) Glucosyltransferase-dependent and independent effects of Clostridioides difficile toxins during infection. PLOS Pathogens, 18 (2). e1010323. ISSN 1553-7366

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Abstract

Clostridioides difficile infection (CDI) is the leading cause of nosocomial diarrhea and pseudomembranous colitis in the USA. In addition to these symptoms, patients with CDI can develop severe inflammation and tissue damage, resulting in life-threatening toxic megacolon. CDI is mediated by two large homologous protein toxins, TcdA and TcdB, that bind and hijack receptors to enter host cells where they use glucosyltransferase (GT) enzymes to inactivate Rho family GTPases. GT-dependent intoxication elicits cytopathic changes, cytokine production, and apoptosis. At higher concentrations TcdB induces GT-independent necrosis in cells and tissue by stimulating production of reactive oxygen species via recruitment of the NADPH oxidase complex. Although GT-independent necrosis has been observed in vitro, the relevance of this mechanism during CDI has remained an outstanding question in the field. In this study we generated novel C. difficile toxin mutants in the hypervirulent BI/NAP1/PCR-ribotype 027 R20291 strain to test the hypothesis that GT-independent epithelial damage occurs during CDI. Using the mouse model of CDI, we observed that epithelial damage occurs through a GT-independent process that does not involve immune cell influx. The GT-activity of either toxin was sufficient to cause severe edema and inflammation, yet GT activity of both toxins was necessary to produce severe watery diarrhea. These results demonstrate that both TcdA and TcdB contribute to disease pathogenesis when present. Further, while inactivating GT activity of C. difficile toxins may suppress diarrhea and deleterious GT-dependent immune responses, the potential of severe GT-independent epithelial damage merits consideration when developing toxin-based therapeutics against CDI.

Item Type: Article
Identifier: 10.1371/journal.ppat.1010323
Keywords: Peritore-Galve FC, Shupe JA, Cave RJ, Childress KO, Washington MK, et al. (2022) Glucosyltransferase-dependent and independent effects of Clostridioides difficile toxins during infection. PLOS Pathogens 18(2): e1010323. https://doi.org/10.1371/journal.ppat.1010323
Subjects: Medicine and health
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Depositing User: Rory J. Cave
Date Deposited: 04 Apr 2022 10:17
Last Modified: 04 Apr 2022 10:17
URI: https://repository.uwl.ac.uk/id/eprint/8895

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