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 turkey airpods 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 crimson sentry norway maple 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.