Clostridioides 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 virulence factor that contributes to inflammation and tissue damage during disease. Immunization with an inactive TcdB fragment prevents 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 and TcdB during primary and recurrent infection. Here, we used a murine model of disease recurrence to demonstrate that an initial infection induced a serum IgM and mucosal IgA response against the toxin, but a low serum IgG response, which 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, failed to significantly expand the memory B cell compartment. Further, infection failed to stimulate the memory B cell compartment in preimmunized mice, although they were protected against associated disease. These results delineate the key humoral immune events that follow primary and recurrent infection and provide a compelling inverse correlation between B cell memory and disease recurrence.