Date Published: April 24, 2019
Publisher: Public Library of Science
Author(s): Hanne Dubois, Frederic Sorgeloos, Soroush T. Sarvestani, Liesbet Martens, Yvan Saeys, Jason M. Mackenzie, Mohamed Lamkanfi, Geert van Loo, Ian Goodfellow, Andy Wullaert, Megan Baldridge.
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.
Human norovirus infection is the most common cause of food-borne gastroenteritis worldwide, responsible for an estimated 684 million cases per year . While norovirus gastroenteritis is self-limiting in immunocompetent individuals, it can evolve to a seriously debilitating and even life-threatening infection in conditions of genetic or acquired immunosuppression . Moreover, norovirus infections also account for more than 200,000 deaths annually, mostly affecting children below five years of age in developing countries . Despite this significant global socio-economic burden, the cellular processes that are induced upon gastrointestinal norovirus infection are poorly understood.
In this study, we reveal activation of the canonical Nlrp3 inflammasome leading to IL-1β secretion and GSDMD-dependent pyroptotic cell death as a detrimental innate immune response triggered by MNV. Given that several studies demonstrated protective roles for inflammasomes in various viral infections [10–15], our observation that the Nlrp3 inflammasome contributes to MNV-induced lethality in Stat1-/- mice is remarkable. Interestingly however, Influenza infection studies have shown that the level of host IFN responsiveness determines the physiological outcome of inflammasome activation in viral infections. While inflammasome deficiency was detrimental during Influenza infection when compared with wild-type mice [10–12], abrogating inflammasome signaling prevented Influenza-induced lethality in Tlr7-/-Mavs-/- mice that are impaired in mounting type I IFN responses to Influenza . Our study showing that the Nlrp3 inflammasome contributes to lethality upon gastrointestinal MNV infection in IFN-unresponsive Stat1-/- mice is in line with this observation in Influenza-infected mice. Moreover, our observation that STAT1 signaling prevents MAVS-mediated upregulation of pro-IL-1β suggests that enhanced expression of this inflammasome substrate may be one of the reasons why inflammasome activation is detrimental rather than protective in the absence of IFN signaling.