Nlrp3 inflammasome activation and Gasdermin D-driven pyroptosis are immunopathogenic upon gastrointestinal norovirus infection

H Dubois; F Sorgeloos; ST Sarvestani; L Martens; Y Saeys; JM MacKenzie; M Lamkanfi; G Van Loo; I Goodfellow; A Wullaert

Journal article

Nlrp3 inflammasome activation and Gasdermin D-driven pyroptosis are immunopathogenic upon gastrointestinal norovirus infection

H Dubois, F Sorgeloos, ST Sarvestani, L Martens, Y Saeys, JM MacKenzie, M Lamkanfi, G Van Loo, I Goodfellow, A Wullaert

Plos Pathogens | PUBLIC LIBRARY SCIENCE | Published : 2019

DOI: 10.1371/journal.ppat.1007709

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Abstract

Norovirus infection is the leading cause of food-borne gastroenteritis worldwide, being responsible for over 200,000 deaths annually. Studies with murine norovirus (MNV) showed that protective STAT1 signaling controls viral replication and pathogenesis, but the immune mechanisms that noroviruses exploit to induce pathology are elusive. Here, we show that gastrointestinal MNV infection leads to widespread IL-1β maturation in MNV-susceptible STAT1-deficient mice. MNV activates the canonical Nlrp3 inflammasome in macrophages, leading to maturation of IL-1β and to Gasdermin D (GSDMD)-dependent pyroptosis. STAT1-deficient macrophages displayed increased MAVS-mediated expression of pro-IL-1β, faci..

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University of Melbourne Researchers

Jason Mackenzie Author

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Grants

Awarded by UK Research and Innovation

Funding Acknowledgements

AW is supported by the Odysseus grant G.0C49.13N and research grants 3G.0447.18 and 3G.0448.18 from the Fund for Scientific Research-Flanders. AW is a post-doctoral fellow with the Fund for Scientific Research-Flanders in the GvL laboratory. FS was supported by funding from the Biotechnology and Biological Sciences Research Council (ref BB/K002465/1). IG is a Wellcome Senior Fellow and is supported by funding from the Wellcome Trust (ref 207498/Z/17/Z). FS was supported by funding from the Biotechnology and Biological Sciences Research Council UK (Ref: BB/K002465/1). Work in the JMM laboratory is supported by Project Grants 1010327 and 1083139 awarded by the National Health and Medical Council of Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.