Back to Search
Start Over
Clostridioides difficile toxin B subverts germinal center and antibody recall responses by stimulating a drug-treatable CXCR4-dependent mechanism.
- Source :
-
Cell reports [Cell Rep] 2024 May 28; Vol. 43 (5), pp. 114245. Date of Electronic Publication: 2024 May 17. - Publication Year :
- 2024
-
Abstract
- 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.<br />Competing Interests: Declaration of interests K.M.N., M.L.L., and J.D.B. are listed as inventors on provisional US patent OKLA.P0023US.P1 filed on 09/13/23, which is related to the work described here.<br /> (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Mice
Mice, Inbred C57BL
B-Lymphocytes immunology
B-Lymphocytes metabolism
Chemokine CXCL12 metabolism
Clostridium Infections immunology
Clostridium Infections microbiology
Humans
Immunoglobulin G immunology
Immunoglobulin G metabolism
Immunologic Memory
Female
Antibody Formation immunology
Receptors, CXCR4 metabolism
Receptors, CXCR4 immunology
Germinal Center immunology
Bacterial Proteins metabolism
Bacterial Proteins immunology
Bacterial Toxins immunology
Bacterial Toxins metabolism
Clostridioides difficile immunology
Clostridioides difficile pathogenicity
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 43
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 38761377
- Full Text :
- https://doi.org/10.1016/j.celrep.2024.114245