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The Role of Type I Interferon in Regulating Norovirus Infections

Stephanie M. Karst

Noroviruses are responsible for a large majority of non-bacterial gastroenteritis outbreaks worldwide. They are considered to be the leading cause of foodborne disease outbreaks and are classified as category B biodefense agents. Noroviruses pose huge medical and economic burdens to the global community: While they display a rapid course of infection in healthy adults, several risk groups including children, the elderly, and immunocompromised individuals are susceptible to more severe and prolonged infections. Moreover, noroviruses can affect any semiclosed community including nursing homes, schools, disaster relief situations, vacation-based and military settings, and they are a major cause of hospital closures for the purpose of outbreak control. Elucidating the host immune responses contributing to the control of norovirus infections is essential to advance our understanding of norovirus pathogenesis and eventually to the design of effective anti-norovirus therapeutic strategies. Recent work on both human and murine noroviruses has unequivocally demonstrated that type I interferon responses, and in particular STAT1-mediated signaling events, are essential for norovirus control. This regulation is mediated at least in part by direct inhibition of norovirus replication in infected cells. The pattern recognition receptor MDA5 contributes to norovirus recognition, although other as-yet-unidentified host receptors must also be involved. Host genes induced upon type I interferon signaling target norovirus translation independent of the well-characterized antiviral molecule PKR. There is suggestive indirect evidence that noroviruses can delay the induction of type I interferon, but may not encode mechanisms to antagonize interferon-mediated signaling. Future mechanistic studies aimed at elucidating the precise interferon-dependent mechanisms by which host cells target norovirus replication may contribute to the design of effective anti-norovirus therapeutic strategies modeled on this activity. Furthermore, there are ongoing efforts to determine whether exogenous interferon can be used therapeutically in the context of norovirus infections.