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, 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.
Highlights
Human norovirus infection is the most common cause of food-borne gastroenteritis worldwide, responsible for an estimated 684 million cases per year [1]
Using the murine norovirus (MNV) model we showed that MNV infection in macrophages leads to a lytic form of cell death termed pyroptosis as well as to the maturation and release of the pro-inflammatory cytokine IL-1β
Maturation of IL-1β was observed in vivo, after gastrointestinal infection of MNV-susceptible Stat1 knockout mice. We found that these innate immune responses upon MNV infection crucially depended on activation of the Nlrp3 inflammasome leading to Gasdermin D-driven pyroptosis, and inactivating this signaling pathway delayed lethality of MNV-susceptible STAT1 knockout mice after gastrointestinal MNV infection
Summary
Human norovirus infection is the most common cause of food-borne gastroenteritis worldwide, responsible for an estimated 684 million cases per year [1]. Norovirus infections account for more than 200,000 deaths annually, mostly affecting children below five years of age in developing countries [1]. Norovirus challenge studies in human volunteers showed that viral shedding lasts long after the acute vomiting and diarrhea symptoms have subsided, and revealed that in some individuals the viral burden peaks after clinical symptoms had been resolved [3]. This poor correlation between viral titers and gastrointestinal manifestations suggests that in addition to norovirus replication, some of the host innate responses to infection may contribute to provoking pathology. Studies using the murine norovirus (MNV) model showed that Interferon (IFN)-induced STAT1-dependent responses are required for controlling viral replication and associated pathogenesis [4,5,6], but the deleterious innate immune mediators that contribute to norovirus-induced intestinal and systemic inflammation remain to be elucidated
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