Targeted activation of IL-22 producing innate lymphoid cells enhances host resistance against Clostridioides difficile infection

Abstract Clostridioides difficile, the most common hospital acquired pathogen in the United States, infects the gastrointestinal tract following perturbation of the intestinal microbiota causing debilitating, potentially fatal colitis. Primary C. difficile infection has a high recurrence rate following antibiotic treatment, emphasizing the need to develop alternative treatment strategies to reduce the burden on the healthcare system. Innate lymphoid cells (ILCs) are necessary for acute host defense following C. difficile infection and represent a promising therapeutic target to harness the patient’s innate immune defenses to limit disease. Here, using a murine model of C. difficile infection, we report that oral administration of Resiquimod (R848), a TLR-7 agonist previously reported to activate type-3 ILCs (ILC3s), protects mice from lethal C. difficile challenge. R848 treatment did not alter intestinal microbial communities or impact C. difficile burden. R848 treatment conveyed protection via activation of the host immune system in a TLR-7 dependent manner. R848-mediated protection was independent of T and B cells as well as type-I IFN signaling. Mice lacking ILCs, however, did not respond to R848 treatment and remained susceptible to infection, identifying these cells as the key targets of R848 activity. Last, R848 treatment robustly induced ILC3s in the large intestine to produce IL-22 and genetic ablation of IL-22 abrogated R848-mediated protection from C. difficile infection. Combined, these data identify an immunostimulatory molecule that activates the IL-22 producing ILC3s to support host defense against C. difficile infection without causing further dysbiosis of the intestinal microbiota. NIH R01AI158830, R21AI164385