Host Immunity and Immunization Strategies for Clostridioides difficile Infection

Abstract

Clostridioides difficile infection (CDI) represents a significant challenge to public health. C. difficile-associated mortality and morbidity have led the U.S. CDC to designate it as an urgent threat. Moreover, recurrence or relapses can occur in up to a third of CDI patients, due in part to antibiotics being the primary treatment for CDI and the major cause of the disease. In this review, we summarize the current knowledge of innate immune responses, adaptive immune responses, and the link between innate and adaptive immune responses of the host against CDI. The other major determinants of CDI, such as C. difficile toxins, the host microbiota, and related treatments, are also described. Finally, we discuss the known therapeutic approaches and the current status of immunization strategies for CDI, which might help to bridge the knowledge gap in the generation of therapy against CDI.

Keywords: Clostridium difficile; fecal microbiota transplant; host immune response; innate lymphoid cells; microbiome; vaccine.

FIG 1

The gut microbiota orchestrates an immune circuit necessary for Tfh and Bmem cell function to generate protective adaptive immunity during CDI. (Left) With nonrecurrent cases, gut microbiota and epithelial cell-derived IL-33 and IL-25 induce Th2 responses and innate lymphoid cells type 2 (ILC2s). ILC2s interact with T cells via MHC-II, CCL5, PD-1/PD-L1, OX-40/OX-40L, CD80, and CD86. ILC2s interact with B cells via ICOS/ICOSL and IL-5, resulting in B cell activation, isotype switching, survival, self-renewal, and antibody secretion. Tfh and Bmem cells collaborate in the mesenteric lymph nodes, homing to the site of infection, and produce the anti-TcdB neutralizing antibody needed to contain CDI. In mesenteric lymph nodes or secondary lymphoid tissues, Tfh cells interact with B cells and favor the development of plasma cells. Afterward, these plasma cells reach the colonic lamina propria where they are able to produce and release large amounts of anti-TcdB neutralizing antibody leading to disease resolution. In the absence of appropriate gut microbiota, adaptive immune cells fail to respond to infection to generate sufficient immunity for a recall response during recurrent disease. (Right) (Relapsed) patients with recurrence episodes have a deficient memory B cell response. The reduction of these cells along with the failure in the production of IgA, IgG, and IgM Abs allows C. difficile to replicate and induce epithelial damage. Also, the microbiota produces acetate by fermenting dietary fibers that activate FFAR2 receptor signaling present on ILC3s. ILC3s promote T cell-dependent IgA production by regulating T cell homing to the gut and may help in epithelial healing and protection from C. difficile through the release of IL-22.

FIG 2

Microbiota-driven gut homeostasis. Commensal antigens induce tolerogenic DCs to produce TGF-β and retinoic acid, which contributes to Treg cell differentiation. Treg cells inhibit Th1 and Th17 responses to maintain gut homeostasis. On the other hand, activation of commensal-induced ILC2 produces IL-4, IL-5, and IL-13 and also activated the number of eosinophils that release IL-4, skewing the Th17 and Th1 to Th2 response that mediates protection. Furthermore, IL-13 and IL-4 induce alternatively activated macrophages that help in epithelial repair and produce IL-10. IL-10 further inhibits type 3 responses and maintains gut homeostasis.

FIG 3

Past, present, and future of C. difficile vaccine in development. Two major phase III trials for C. difficile vaccines from Sanofi and Pfizer were determined futile and halted. The vaccines from Shire are in a phase III trial and one from Valneva was phase II terminated. Many vaccines have been tested at the murine model level by adding a third CDT toxin of C. difficile. Even nontoxinogenic strains with a recombinant vector containing domains of toxin A and toxin B were tested as potent vaccine candidates.