Host humoral immune suppression by Clostridioides difficile Toxin A and Toxin B

Abstract

Abstract Gram-positive Clostridioides difficile is the greatest cause of nosocomial enteric disease in the US and is associated with a high rate of morbidity and mortality. During C. difficile infection (CDI), two secreted toxins (TcdA and TcdB) drive pathogenesis. Although T-dependent humoral immunity, specifically high affinity TcdA- and TcdB-neutralizing IgG, is the best correlation for protection against CDI recurrence, this response is commonly lacking following CDI in both mice and patients, leading to a high chance of recurrence. We previously showed that in murine CDI, there was a lack of T follicular helper (Tfh) cell differentiation, reduced IgG class-switching, poor toxin neutralization, and lack of resistance to reinfection. Preliminary data also suggested that TcdB inhibited IgG responses following vaccination against C. difficile. We therefore hypothesize that TcdA and/or TcdB suppress C. difficile-specific T-dependent humoral immunity. Following either CDI or intraperitoneal injection with TcdA or TcdB, immune cells from mesenteric lymph nodes were analyzed for changes in gene expression. Changes in dendritic cell maturation markers were observed in the presence of TcdB but not TcdA. Multi-targeting mRNA profiling showed altered expression of antigen presentation and CD4+ T cell activation genes. Only one of the known TcdB cell entry receptors was expressed by immune cells, specifically by CD4+ T cells and B cells. Efforts are underway to measure the impact of TcdA and TcdB treatment on CD4+ T cell differentiation, Tfh proliferation, and T-B cell interactions. Our data indicate that toxins may hamper neutralizing IgG production by affecting multiple aspects of T-dependent humoral immunity. This work was supported by NIH grants AI134719 (M.L.L.) and AI119048 (J.D.B.).