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PLoS Pathog. 2019 Apr 24;15(4):e1007709. doi: 10.1371/journal.ppat.1007709. eCollection 2019 Apr.

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

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Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium.
Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium.
Janssen Immunosciences, World Without Disease Accelerator, Janssen Pharmaceutica, Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium.
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Ghent Gut Inflammation Group (GGIG), Ghent University, Ghent, Belgium.


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, facilitating elevated Nlrp3-dependent release of mature IL-1β upon MNV infection. Accordingly, MNV-infected Stat1-/- mice showed Nlrp3-dependent maturation of IL-1β as well as Nlrp3-dependent pyroptosis as assessed by in vivo cleavage of GSDMD to its active N-terminal fragment. While MNV-induced diarrheic responses were not affected, Stat1-/- mice additionally lacking either Nlrp3 or GSDMD displayed lower levels of the fecal inflammatory marker Lipocalin-2 as well as delayed lethality after gastrointestinal MNV infection. Together, these results uncover new insights into the mechanisms of norovirus-induced inflammation and cell death, thereby revealing Nlrp3 inflammasome activation and ensuing GSDMD-driven pyroptosis as contributors to MNV-induced immunopathology in susceptible STAT1-deficient mice.

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Conflict of interest statement

The authors have declared that no competing interests exist.

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