Abstract
The inflammasome machinery has recently been recognized as an emerging pillar of innate immunity. However, little is known regarding the interaction between the classical interferon (IFN) response and inflammasome activation in response to norovirus infection. We found that murine norovirus (MNV-1) infection induces the transcription of IL-1β, a hallmark of inflammasome activation, which is further increased by inhibition of IFN response, but fails to trigger the release of mature IL-1β. Interestingly, pharmacological inflammasome inhibitors do not affect viral replication, but slightly reverse the inflammasome activator lipopolysaccharide (LPS)-mediated inhibition of MNV replication. LPS efficiently stimulates the transcription of IFN-β through NF-ĸB, which requires the transcription factors IRF3 and IRF7. This activates downstream antiviral IFN-stimulated genes (ISGs) via the JAK-STAT pathway. Moreover, inhibition of NF-ĸB and JAK-STAT signaling partially reverse LPS-mediated anti-MNV activity, suggesting additional antiviral mechanisms activated by NF-ĸB. This study reveals additional insight in host defense against MNV infection.
Highlights
Norovirus is a major cause of epidemic nonbacterial gastroenteritis worldwide
Innate immune response provides the first line of defense against viral infection through the recognition of pathogen associated molecular patterns (PAMPs) by its pattern recognition receptors (PRRs) including the recognized Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I like receptor (RLRs) and the cyclic GMP-AMP synthase (Wu and Chen, 2014)
We first determined the expression of IL-1β and IL-18 as markers of inflammasome activation in J774A.1 cells treated with LPS and adenosine 5-triphosphate disodium salt hydrate (ATP), the potent activators for inflammasome activation
Summary
Norovirus is a major cause of epidemic nonbacterial gastroenteritis worldwide. Currently, no vaccination or specific antiviral treatment is available except for supportive care and supplementation of fluids, exerting a great global economic burden and significant impact on public health (Karst et al, 2014). The lack of a robust human norovirus (HuNV) cell culture system is a key bottleneck for norovirus research. Recent studies have achieved some success in culturing HuNV in intestinal enteroid or B cells with modest viral replication level (Ettayebi et al, 2016; Jones et al, 2015), and in zebrafish larvae (Van Dycke et al, 2019) and human induced pluripotent stem cell-derived intestinal epithelial cells (Sato et al, 2019), but these systems have not been widely used. Murine norovirus (MNV), permissive for replication in both cell culture and small-animal models, shares similar structural, biochemical and genetic features with HuNV, and has become a useful model for studying norovirus biology and associated pathology (Wobus et al, 2004, 2006)
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