Defining innate immune signaling, viral infection susceptibility, and infection control across mammals

Project 2. Defining innate immune signaling, viral infection susceptibility, and infection control across mammals Summary The focus of Project 2 is to determine the actions of cell-intrinsic innate immunity, interferon (IFN), and viral countermeasures of innate immune evasion of virus infection across model RNA viruses and diverse mammalian species. Virus infections drive enormous evolutionary pressure on both host and virus genomes. As such, host innate immune genes are highly divergent across host and virus immune antagonist genes also vary across viruses within the same family. The innate immune system can present a significant barrier to viruses crossing into new species. This project will use data from Core B to define virus-species pairs where innate immunity presents a barrier and Core C to identify genes and pathways for evaluation in mechanistic studies. We will then evaluate mechanisms of host control of virus infection and virus success at evading these responses through two independent aims. Aim 1 will evaluate species-specific effector mechanisms of IFN actions that control virus infection and will uncover mechanisms of action using comparative analyses and measuring the stage of the virus life cycle that is targeted. Aim 2 will determine the role of viral factors of innate immune evasion which support species-specific virus infection. This aim will also establish the zoonic potential of each species for human infection. Together, Project 2 studies will reveal conserved and divergent innate immune and IFN effector mechanisms of alphavirus and flavivirus control and viral evasion across species. Our results will link to Project 1 studies to define mechanisms of viral pathogenesis and will inform consideration of therapeutic strategies for mitigating infection and disrupting zoonotic virus transmission.