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Norman, Kaylee M.; Lang, Gillian A.; Shadid, Tyler M.; Honold, Sydney T.; Reel, Jessica M.; Cox, Maureen A.; Ballard, Jimmy D.; Lang, Mark L.
Cell reports (Cambridge), 05/2024, Letnik: 43, Številka: 5Journal Article
Recurrent Clostridioides difficile infection (CDI) results in significant morbidity and mortality. We previously established that CDI in mice does not protect against reinfection and is associated with poor pathogen-specific B cell memory (Bmem), recapitulating our observations with human Bmem. Here, we demonstrate that the secreted toxin TcdB2 is responsible for subversion of Bmem responses. TcdB2 from an endemic C. difficile strain delayed immunoglobulin G (IgG) class switch following vaccination, attenuated IgG recall to a vaccine booster, and prevented germinal center formation. The mechanism of TcdB2 action included increased B cell CXCR4 expression and responsiveness to its ligand CXCL12, accounting for altered cell migration and a failure of germinal center-dependent Bmem. These results were reproduced in a C. difficile infection model, and a US Food and Drug Administration (FDA)-approved CXCR4-blocking drug rescued germinal center formation. We therefore provide mechanistic insights into C. difficile-associated pathogenesis and illuminate a target for clinical intervention to limit recurrent disease. Display omitted •C. difficile toxin B (TcdB2) suppresses antibody recall responses•TcdB2 blocks germinal center formation•TcdB2 alters B cell CXCR4-mediated cell migration•A CXCR4-blocking drug rescues germinal center formation Norman et al. use mouse models of C. difficile vaccination and infection to delineate a CXCR4-dependent mechanism by which the secreted toxin TcdB2 suppresses germinal center formation and antibody recall responses. Germinal centers were rescued by a CXCR4-blocking drug, suggesting a therapeutic avenue for prevention of recurrent C. difficile infection.
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in: SICRIS
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