IL-33 drives group 2 innate lymphoid cell-mediated protection during Clostridium difficile infection

Alyse L. Frisbee, Mahmoud M. Saleh, Mary K. Young, Jhansi L. Leslie, Morgan E. Simpson, Mayuresh M. Abhyankar, Carrie A. Cowardin, Jennie Z. Ma, Patcharin Pramoonjago, Stephen D. Turner, Alice P. Liou, Erica L. Buonomo and William A. Petri ()
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Alyse L. Frisbee: University of Virginia Health System
Mahmoud M. Saleh: University of Virginia Health System
Mary K. Young: University of Virginia Health System
Jhansi L. Leslie: University of Virginia Health System
Morgan E. Simpson: University of Virginia Health System
Mayuresh M. Abhyankar: University of Virginia Health System
Carrie A. Cowardin: University of Virginia Health System
Jennie Z. Ma: University of Virginia School of Medicine
Patcharin Pramoonjago: University of Virginia Health System
Stephen D. Turner: University of Virginia School of Medicine
Alice P. Liou: Seres Therapeutics
Erica L. Buonomo: University of Virginia Health System
William A. Petri: University of Virginia Health System

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10733-9

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