Abstract
Clostridium difficile (C. difficile) incidence has tripled over the past 15 years and is attributed to the emergence of hypervirulent strains. While it is clear that C. difficile toxins cause damaging colonic inflammation, the immune mechanisms protecting from tissue damage require further investigation. Through a transcriptome analysis, we identify IL-33 as an immune target upregulated in response to hypervirulent C. difficile. We demonstrate that IL-33 prevents C. difficile-associated mortality and epithelial disruption independently of bacterial burden or toxin expression. IL-33 drives colonic group 2 innate lymphoid cell (ILC2) activation during infection and IL-33 activated ILC2s are sufficient to prevent disease. Furthermore, intestinal IL-33 expression is regulated by the microbiota as fecal microbiota transplantation (FMT) rescues antibiotic-associated depletion of IL-33. Lastly, dysregulated IL-33 signaling via the decoy receptor, sST2, predicts C. difficile-associated mortality in human patients. Thus, IL-33 signaling to ILC2s is an important mechanism of defense from C. difficile colitis.
Highlights
Clostridium difficile (C. difficile) incidence has tripled over the past 15 years and is attributed to the emergence of hypervirulent strains
We demonstrate that IL-33 signaling is a critical mechanism of intestinal protection during C. difficile colitis via the action of ILC2s
We see that IL-33 activates ILC2s in the large intestine and induces type-2 repair pathways that protect from toxin-mediated epithelial damage
Summary
Clostridium difficile (C. difficile) incidence has tripled over the past 15 years and is attributed to the emergence of hypervirulent strains. Many pro-inflammatory pathways such as Th-17-associated IL-23, IL-17, and toll-like receptor 2 (TLR2) signaling exacerbate C. difficile-associated mortality[6,13,14,15] Several of these murine studies have been corroborated in human patients with IFN-γ, IL-5 and peripheral eosinophil counts being associated with less severe infection yet pro-inflammatory cytokines, such as IL-8, IL-2, and IL-6 being associated with poor prognosis[15,16,17,18]. We demonstrate a connection between fecal microbiota transplantation (FMT) therapy and IL-33 levels within the colon, indicating a potentially targetable approach for increasing colonic IL-33 with rationally designed, next-generation microbial cocktails These studies demonstrate that IL-33 signaling to ILC2s is an essential pathway for recovery from C. difficile-associated colitis
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