Influenza virus infection causes yearly infections characterized by the abrupt onset of symptoms including fever, myalgia, headache, malaise and chills. Recently, highly pathogenic avian influenza viruses have arisen in aquatic birds and the subsequent zoonotic infections of humans have raised fear of a human pandemic. The fatality rate in humans is very high and while the reason for the virulence is not known, immune disregulation has been implicated. The immune response to the influenza virus begins with an innate response consisting of the release of type 1 interferon and proinflammatory cytokines but most studies show that an adaptive response is essential for viral clearance. However, evidence suggests that early events are crucial to control virus replication and initiate the adaptive response. We have focused our recent investigations on the very early events that occur in mice infected with influenza virus PR8. We have observed a delayed inflammatory response that we ascribe to the impact of the immune antagonist protein, NS1. Once inflammation has been activated high levels of cytokine/chemokines/growth factors can be demonstrated in the lungs and blood. This is followed by an influx of monocytes to the lungs that continue to arrive throughout the course of infection. Cells, in bone marrow and in blood, express an interferon signature indicating exposure to interferon that renders them resistant to virus infection. Our data suggest that they will respond much more vigorously when exposed to virus. In this application we propose to complete a comprehensive study of these early immune events following virus infection. We will take advantage of recently generated type I and type III knockout mice (dKO) to analyze the interferon independent immune pathway and by extension the importance of interferon signaling to anti-viral immunity. Moreover, using influenza virus lacking the immune antagonist protein, NS1, to infect dKO mice, we will measure the impact of NS1 on interferon independent immunity. In aim 3 we will study the early events in the immune response of mice following infection with highly pathogenic avian influenza virus (HPAI). The cytokine response will be studied for disregulation with a particular focus on the relationship of interferon to inflammatory cytokines. Finally, we will try to determine the impact that the HPAI virus has on the early events of immune activation and the triggering of the T cell response.