Nlrp3 inflammasome activation and Gasdermin D-driven pyroptosis are immunopathogenic upon gastrointestinal norovirus infection.
Sarvestani, Soroush T
Public Library of Science (PLoS)
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Dubois, H., Sorgeloos, F., Sarvestani, S. T., Martens, L., Saeys, Y., Mackenzie, J. M., Lamkanfi, M., et al. (2019). Nlrp3 inflammasome activation and Gasdermin D-driven pyroptosis are immunopathogenic upon gastrointestinal norovirus infection.. PLoS pathogens, 15 (4), e1007709. https://doi.org/10.1371/journal.ppat.1007709
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.
Gastrointestinal Tract, Cells, Cultured, Macrophages, Animals, Mice, Inbred C57BL, Mice, Knockout, Mice, Norovirus, Caliciviridae Infections, Intracellular Signaling Peptides and Proteins, Phosphate-Binding Proteins, STAT1 Transcription Factor, Apoptosis Regulatory Proteins, Interleukin-1beta, Inflammasomes, Pyroptosis, NLR Family, Pyrin Domain-Containing 3 Protein
Wellcome Trust BBSRC
Wellcome Trust (207498/Z/17/A)
Wellcome Trust (207498/Z/17/Z)
BBSRC (via Imperial College London) (2943027)
Wellcome Trust (097997/Z/11/Z)
Embargo Lift Date
External DOI: https://doi.org/10.1371/journal.ppat.1007709
This record's URL: https://www.repository.cam.ac.uk/handle/1810/290818