C. difficile infection induces an inferior IgG response to that induced by immunization and is associated with a lack of T follicular helper cell and memory B cell expansion.

The intracellularly-active bacterial toxin, TcdB, is a major Clostridioides difficile virulence factor that contributes to inflammation and tissue damage during disease. Immunization with an inactive TcdB fragment prevents C. difficile infection (CDI)-associated pathology. The protective immune response against inactive TcdB involves development of antigen-specific memory B cells and long-lived plasma cells that encode TcdB-neutralizing antibodies. Unlike the response to inactive TcdB, very little is known about the host humoral immune response to C. difficile and TcdB during primary and recurrent infection. Herein we used a murine model of C. difficile disease recurrence to demonstrate that an initial infection induces a serum IgM and mucosal IgA response against the toxin but a low serum IgG response, and this is associated with a lack of protection against disease during reinfection. Infection induced a partial expansion of the T follicular helper cell compartment, essential for B cell memory responses and consistent with that, it failed to significantly expand the memory B cell compartment. Furthermore infection failed to stimulate the memory B cell compartment in pre-immunized mice although they were protected against associated disease. These results delineate the key humoral immune events that follow primary and recurrent C. difficile infection and provide a compelling inverse correlation between B cell memory and disease recurrence.