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| Status |
Public on Apr 25, 2024 |
| Title |
Clostridioides difficile Toxin B subverts germinal center formation and antibody recall responses by stimulating a drug-treatable CXCR4-dependent mechanism |
| Organism |
Mus musculus |
| Experiment type |
Other
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| 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.
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| Overall design |
Female mice (n=4 per group) were given 200 µl PBS vehicle control, 10 ng D270N, or 10 ng TcdB2 in PBS by the s.c. route. Seven days post treatment, RNA was purified from aLNs and iLNs. Gene expression was quantified using the Nanostring™ nCounter SPRINT profiler platform.
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| Contributor(s) |
Norman K, Lang M |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Apr 11, 2024 |
| Last update date |
Apr 26, 2024 |
| Contact name |
Kaylee M Norman |
| E-mail(s) |
Kaylee-norman@ouhsc.edu
|
| Phone |
19189987829
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| Organization name |
University of Oklahoma Health Sciences Center
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| Department |
Microbiology and Immunology
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| Lab |
Lang Lab
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| Street address |
940 Statond L Young Blvd
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| City |
Oklahoma City |
| State/province |
OK |
| ZIP/Postal code |
73104 |
| Country |
USA |
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| Platforms (1) |
| GPL25266 |
NanoString Mouse nCounter Myeloid Innate Immunity Panel NS_Mm_Myeloid_V2.0 |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA1099250 |
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