Mouse adenovirus type 1 (MAV-1) provides an ideal animal model system for studying the molecular basis of adenoviral pathogenesis, which cannot be pursued using the species-specific human adenoviruses. Genetic and biochemical approaches are being used to examine the viral and host factors involved in MAV-1 pathogenesis, which is characterized by acute and persistent infections. The first MAV-1 viral mutants have been isolated and are being used to investigate the contributions of specific viral genes to the infectious process in mice. There are three specific aims: 1. Characterize the host response to MAV-1 infection, particularly components of innate and adaptive immunity. The specific cell type(s) in the spleen which are infected by MAV-1 will be identified. Mice with deficiencies in immune system components will be tested for their susceptibility to MAV-1 infection. The effects of two key cytokines, tumor necrosis factor-( and interferons, on viral infections will be investigated. The sensitivity of MAV-1 infected cells to natural killer cell lysis will be determined. 2. Determine the contributions of MAV-1 early region 1A (E1A) and early region 3 (E3) gene products to viral pathogenesis. Various virus-host interactions identified for E1A and E3 of human adenoviruses implicate these regions in pathogenesis of acute and persistent infections, and experiments show that MAV-1 viruses with mutations in E1A or E3 have altered lethality for adult mice. Organ or tissue tropism of mutant viruses and expression of their viral gene products in mice will be compared to that of wild-type virus. The ability of wild-type and mutant viruses to produce persistent infections will be examined. Specific cellular proteins which interact with the E1A and E3 proteins will be identified. 3. Investigate the host genetics of susceptibility to MAV-1 infection. Mouse strains with different susceptibilities to wild-type MAV-1 infection have been identified. Additional inbred strains of mice will be tested for susceptibility to MAV-1. The strains chosen will enable determination of whether H-2 haplotype is a factor in susceptibility, and will form the basis for genetic studies to map genes for susceptibility to MAV-1. The combined approaches of characterizing the host response to wild-type MAV-1 infection and investigating virus-host interactions using both viral and host genetics will contribute to the understanding of mechanisms involved in infectious disease.
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