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Nat Commun. 2019 Jun 20;10(1):2712. doi: 10.1038/s41467-019-10733-9.

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

Author information

1
Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA, 22908, USA.
2
Department of Medicine, University of Virginia Health System, Charlottesville, VA, 22908, USA.
3
Department of Pathology, University of Virginia Health System, Charlottesville, VA, 22908, USA.
4
Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
5
Seres Therapeutics, Cambridge, 02139, MA, USA.
6
Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA, 22908, USA. wap3g@virginia.edu.
7
Department of Medicine, University of Virginia Health System, Charlottesville, VA, 22908, USA. wap3g@virginia.edu.
8
Department of Pathology, University of Virginia Health System, Charlottesville, VA, 22908, USA. wap3g@virginia.edu.

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.

PMID:
31221971
PMCID:
PMC6586630
DOI:
10.1038/s41467-019-10733-9
[Indexed for MEDLINE]
Free PMC Article

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