Virus-host interactions in frog virus 3 infected cells

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Background: The goal of this proposal is to understand virus-host interactions employed by a relatively unstudied group of large DNA viruses - the Iridoviridae family. Understanding virus-host interacting genes will allow us to explore novel anti-viral strategies, provide new insight into the function of the immune system, and understand how virus infections lead to viral pathogenesis. Although a number of potential Iridoviridae modulators of host anti-viral mechanisms have been identified based on sequence similarity to other viral or cellular genes, few of these genes have been characterized. Therefore, we will use frog virus 3 (FV3), the best-studied member of the Iridoviridae family, to investigate viral modulators of host defense mechanisms. This proposal will characterize the FV3 gene 75L. Previously, our lab showed that 75L binds to LITAF and that the presence of an FV3 infection induces the expression of LITAF. Hypothesis: We hypothesize that LITAF is part of a conserved cellular defense pathway as its expression is turned on after FV3 infection. We further hypothesize that 75L may antagonize LITAF's function since we have shown that 75L binds to LITAF. In this proposal we will explore whether FV3-75L can inhibit LITAF function. We will also determine whether LITAF represents an uncharacterized cellular host defense mechanism. To achieve these goals, we propose to: 1) Determine if 75L inhibits LITAF function. LITAF has been shown to function in the degradation of a variety of cell surface receptors and induce TNF-a expression. We will determine whether 75L can inhibit these functions. 2) Determine if LITAF affects FV3 replication. Using a variety of assays that monitor different stages of the viral replication cycle, we will determine if viral replication is impaired when 75L protein is reduced or absent. 3) Determine how LITAF is induced upon viral infection. Since LITAF is expressed in response to an FV3 infection, we wanted to determine how an FV3 infection induces LITAF. To test this, we will determine if FV3 induces LITAF through the known pathways that stimulate LITAF expression. Significance: The research outlined in this proposal is aimed at characterizing virus-host interacting genes in the Iridoviridae. This proposal focuses on FV3 and its interactions with LITAF. Since the function of LITAF during a viral infection is unknown, our research will not only elucidate the biological function of LITAF, but will also clarify how 75L mediates the inhibition of LITAF. In addition, since mutations in LITAF can cause the human neurodegenerative disease Charcot-Marie Tooth disease (CMT), our continued characterization of LITAF will help in understanding how mutations in LITAF cause CMT and provide insight into potential therapies for this disease.