Leukotrienes in Innate and Adaptive Antiviral Immunity

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DESCRIPTION (provided by applicant): Viral infections cause widespread death and disease in the human population. The long-range goal of our program is to define the cellular and molecular mechanisms involved in the generation of an efficient protective antiviral immune response. An antiviral immune response is comprised of innate and adaptive components. In the absence of an effective innate antiviral response the efficacy of the subsequent adaptive response is blunted. A major component of the innate inflammatory immune response is the release of bioactive arachidonic acids metabolites mediators, including leukotrienes. Leukotrienes can mediate both the local inflammatory response that can slow virus replication, and the migration of antigen presenting cells that are vital for the initiation of a productive adaptive antiviral response. Knowledge of the processes involved in successful generation of a protective antiviral immune response is incomplete with an understanding of the role of leukotrienes in the initiation of innate and adaptive responses. To date, the role of these innate inflammatory mediators in initiation of a protective antiviral immune response is unknown. Our current objective is to examine the role leukotrienes in the initiation of both the innate and adaptive immune responses to virus infection. The hypothesis in our studies is that leukotrienes function to reduce the severity of a viral infection in the skin, in addition to their role in stimulating the exodus of antigen bearing cells that are then able to stimulate a productive antiviral T cell response. To achieve this objective, three specific aims are proposed: (I) To determine the role of cysteinyl leukotrienes in inflammation following dermal infection with vaccinia virus; (II) To determine the role of leukotrienes in plasmacytoid dendritic cell distribution and function following dermal virus infection and; (III) To determine the role of cysteinyl leukotrienes in the transport of antigen from a dermal site of virus infection to the lymph node, and subsequent T cell activation. The rationale for the proposed research is that an understanding of the role of leukotrienes in antiviral responses is critical for the rationale designs of antiviral drugs and vaccines. At the completion of this project we will expect to have identified the mechanisms by which leukotrienes mediate innate and adaptive antiviral immunity.