Engagement of the innate immune response by viral infection is a critical nexus of disease pathogenesis. Central unanswered questions in viral pathogenesis are how an infected cell is influenced to either enter an antiviral state or undergo apoptosis and the implication of this decision on viral disease mechanisms. Mammalian reoviruses serve as models for studies of viral pathogenesis and are exquisitely suitable for studies of the innate immune response to viral infection. Reoviruses elicit a strong interferon response by activating transcription factors, including IRF-3, which facilitate interferon-beta production. This response modulates reovirus infection and pathogenesis in a tissue-specific manner. However, the initial triggers of signaling cascades leading to transcriptional activation and the mechanisms of interferon-mediated modulation of reovirus infection and disease are not known. We propose to define viral and cellular determinants of IRF-3 activation following reovirus infection and determine the pathological significance of this cellular response.
Two specific aims are proposed. In the first, mechanisms of reovirus-induced IRF-3 activation will be determined. In the second, the role of IRF-3 activation in reovirus apoptosis and virulence in vivo will be determined. Together, these studies will provide new insights into the interface between the innate antiviral response, cell death pathways, and viral disease pathogenesis. ? ? ?
