Regulation of innate immunity and the outcome of RNA virus infection

Innate immune defenses are essential for resistance to viruses and can be triggered through the actions of the cytoplasmic helicases RIG-I and MDA5. Signaling by each is initiated by the recognition of viral products such as RNA and occurs through downstream interaction with the IPS-1 adaptor protein. We have directly compared innate immune signaling requirements of RIG-I, MDA5, and IPS-1 by human pathogen viruses of the Flaviviridae, Orthomyxoviridae, Paramyxoviridae, and Reoviridae. In cultured cells, IPS-1 was essential for innate immune signaling of downstream IRF-3 activation and interferon-stimulated gene expression but the requirement for RIG-I and MDA5 was variable. While RIG-I or MDA5 were individually dispensable for signaling triggered by reovirus, West Nile virus, and Dengue virus, RIG-I was essential for signaling by hepatitis C virus (HCV), influenza A virus (FluA), influenza B virus, and human respiratory syncytial virus. Functional genomics analyses identified shared and unique biosets of cellular genes triggered during infection by these viruses whose expression was strictly dependent on RIG-I and are involved in processes of innate or adaptive immunity, apoptosis, cytokine signaling, and inflammation. Our studies show that HCV and FluA infection each impart control of the RIG-I pathway, and that differential regulation of innate immunity through viral triggering and control of RIG-I signaling is a major determinant of infection outcome. Our studies indicate that expression and function of immune effector genes of the RIG-I pathway are critical determinants of immunity or pathogenesis of RNA virus infection.