Norman et al Clostridioides difficile Toxin B subverts germinal center and antibody recall responses by stimulating a drug-treatable CXCR4-dependent mechanism

Description

Raw data for the Cell Reports manuscript concerning impact of TcdB2 on germinal center reactions. The PDF attachment included (Norman et al project metadata 110623) lists all information needed to analyze and interpret the raw data and is broken down figure by figure corresponding to its organization in the manuscript. On 04/04/24, this entry was amended to add a PDF of the project metadata corresponding to the manuscript revisions (Norman et al project metadata ADDENDUM 040424) and to add raw data corresponding to new experiments that were added during the course of revision. On 04/26/24 following provisional acceptance of the revised manuscript, the final dataset was re-uploaded. PROJECT SUMMARY: Recurrent Clostridioides difficile infection (CDI) results in significant morbidity and mortality. We previously established that CDI in mice did not protect against reinfection and was associated with poor pathogen-specific B cell memory (Bmem), recapitulating our observations with human Bmem. Herein, we demonstrate that the secreted toxin TcdB2 is responsible for subversion of Bmem responses. TcdB2 from an endemic C. difficile strain delayed 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 an 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.

Steps to reproduce

Please refer to attached document: Norman et al project metadata 110623

Institutions

Categories

Funding

Licence