Clostridioides difficile toxin B subverts germinal center and antibody recall responses by stimulating a drug-treatable CXCR4-dependent mechanism

Clostridioides difficile toxin B subverts germinal center and antibody recall responses by stimulating a drug-treatable CXCR4-dependent mechanism

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Summary: 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), flavored-lube 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 Gastrointestinal - Antacid 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.