Abstract
Noroviruses are important human pathogens responsible for most cases of viral epidemic gastroenteritis worldwide. Murine norovirus-1 (MNV-1) is one of several murine noroviruses isolated from research mouse facilities and has been used as a model of human norovirus infection. MNV-1 infection has been shown to require components of innate and adaptive immunity for clearance; however, the initial host protein that recognizes MNV-1 infection is unknown. Because noroviruses are RNA viruses, we investigated whether MDA5 and TLR3, cellular sensors that recognize dsRNA, are important for the host response to MNV-1. We demonstrate that MDA5−/− dendritic cells(DC) have a defect in cytokine response to MNV-1. In addition, MNV-1 replicates to higher levels in MDA5−/− DCs as well as in MDA5−/− mice in vivo. Interestingly, TLR3−/− DCs do not have a defect in vitro, but TLR3−/− mice have a slight increase in viral titers. This is the first demonstration of an innate immune sensor for norovirus and shows that MDA5 is required for the control of MNV-1 infection. Knowledge of the host response to MNV-1 may provide keys for prevention and treatment of the human disease.
Highlights
Norwalk virus and other human noroviruses are common human pathogens responsible for most of the nonbacterial epidemic gastroenteritis in both developed and developing countries [1,2,3,4,5]
Because MDA5 [45,46,47,48], and TLR3 [49,50] have been shown to play a role in host response to other RNA viruses we investigated if these sensors might be involved in norovirus recognition in vitro and in vivo using the murine norovirus-1 (MNV-1) model system
In this study we demonstrate that MDA5 is the predominant sensor of MNV-1 and initiates the innate immune response against the virus, and that TLR3 may play a role in the response to MNV-1 in certain tissues
Summary
Norwalk virus and other human noroviruses are common human pathogens responsible for most of the nonbacterial epidemic gastroenteritis in both developed and developing countries [1,2,3,4,5]. Norovirus infection can result in vomiting, diarrhea, fever, malaise, and abdominal pain within 24 hours after infection. These symptoms usually clear within 48 hours, but the virus can persist asymptomatically for 3–6 weeks post-infection [6,7]. Until recently the inability to culture human noroviruses has prevented investigation into its pathogenicity. Norovirus genomes are covalently linked at the 59 end to a viral nonstructural protein VPg [10]. ORF1 encodes a polyprotein that is cleaved into at least six nonstructural proteins by the viral 3C-like protease [15,16,17,18]. An additional ORF, ORF4 was recently discovered in the MNV genome the function of this ORF has yet to be characterized [14]
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