EXCEED THE SPACE PROVIDED. This proposal is designed to investigate the murine CD8+ T cell response in the lungs and draining lymph nodes after lethal and sub lethal type A influenza virus infection and to define the mechanism for the impaired CD8+ T cell response after lethal infection. It is predicated upon our recent observations implicating the response of airway dendritic cells (ADC) early in the course of pulmonary virus infection (i.e. either the first 24 hours of infection) as a critical regulator of the subsequent development of an effective anti-viral CD8+ T cell response. The underlying hypothesis is that high-level exposure (infection) of ADC in the lungs early in pulmonary influenza infection, alters the maturation/activation or function of ADC resulting in defective induction of a protective anti-viral CD8+ T cell response by responding ADC. Our experimental approach will be to examine the response of DC to influenza infection at different multiplicities (MOI) in vitro and the response of ADC to lethal/sub lethal infection in vivo for maturation/activation (i.e. DC activation marker expression), function (i.e. cytokine synthesis) and for the tempo and magnitude of viral gene expression (i.e. HA, NP, and NS1 proteins). These studies will be coupled with an analysis of the CDS+ T response in the lungs and draining nodes after lethal/sub lethal infection in vivo. Companion studies will examine the activation/differentiation of CD8+ T cells responding in vitro to DC infected at different MOI to elucidate the mechanism of underlying the defective CD8+ T cell response to lethal pulmonary infection. Our ongoing studies in this area will be directed to the following Specific Aims: 1. To characterize the in vivo response to airway dendritic cells to sub lethal type A influenza virus infection; 2. To determine the effect of infectious influenza virus dose on DC phenotype and function in vivo and in vitro; 3. To determine the impact of infecting virus dose on the CD8+ T cell response to influenza virus infection in vivo and in vitro. A thorough understanding of the interplay between CD8+ T ceils and DC in the induction of an effective adaptive immune response is essential for understanding the process of recovery from pulmonary virus infection. Furthermore, detailed information on the impact of infecting virus dose on DC and T cell function will likely provide new insight into the effect of virus inoculum at mucosal surfaces on the subsequent host immune response to a variety of pathogenic human viruses. Finally, this analysis may have important implications for the development of strategies to counteract the use of potentially lethal pulmonary viruses like influenza as biological weapons. PERFORMANCE SITE ========================================Section End===========================================
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