A well characterized murine ocular infection model will be used to study mechanisms involved in HSV-1 induced ocular infection. It is proposed that the proinflammatory cytokine interleukin 1 (IL-1) plays a duel role in virus infection. On the one hand it promotes ocular inflammation. On the other, it enhances defense mechanisms that limit HSV-1 replication and spread. To test this hypothesis a series of experiments focusing on the IL-1 isoforms will be conducted. First, the techniques of in situ hybridization and immunohistology will be used to identify which corneal cells initially produce IL-1alpha and IL-1beta after HSV-1 infection. Experiments will be conducted to determine whether corneal cells express IL-1 receptors in vivo. Next, the IL-1 isoforms will be inoculated into the cornea to test their capacity to stimulate cytokines with proinflammatory and anti-viral activities. Cytokine mRNA will be detected by quantitative PCR while the protein product will be detected by ELISA. Finally, monoclonal antibodies specific for the IL-1 isoforms will be injected intracorneally in order to test how neutralization of endogenously produced IL-1 affects early events in HSV-1 infection. The early events studied in the cornea will be HSV-1 replication, Langerhans cell migration, and proinflammatory cytokine synthesis. Overall, the information gained from these studies will contribute to our long term objectives, which are to develop new strategies for (a) minimizing the corneal inflammatory response, and (b) controlling the replication of this important ocular pathogen.
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