Nlrp3 inflammasome activation and Gasdermin D-driven pyroptosis are detrimental in gastrointestinal norovirus infection

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-dependent pyroptosis. STAT1-deficient macrophages displayed increased Nlrp3 inflammasome responses, and inactivation of either Nlrp3 or Gasdermin D delayed lethality of Stat1-/- mice after gastrointestinal MNV infection. These results reveal a detrimental role for Nlrp3 inflammasome activation and ensuing Gasdermin D-driven pyroptosis in MNV-induced pathology, suggesting this innate immune signaling axis as a potential therapeutic target in norovirus-induced gastroenteritis.

Authors

Hanne Dubois
Frederic Sorgeloos
Soroush T. Sarvestani
Liesbet Martens,
Yvan Saeys (2,5)
Jason M. Mackenzie
Mohamed Lamkanfi
Geert van Loo (2,6)
Ian Goodfellow
Andy Wullaert

Organisations

Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium. VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium (1)
Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom (2)
Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia (3)
Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium (4)
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium (5)
Ghent Gut Inflammation Group (GGIG), Ghent University, Ghent, Belgium (6)

Presenting author

Hanne Dubois, PhD Student, VIB - Ugent center for inflammation research
hanne.dubois@irc.vib-ugent.be
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