Mouse adenovirus type 1 (MAV-1) causes disease in the newborn or adult mouse by infecting endothelial cells and cells of the monocyte/macrophage lineage throughout the animal. Depending on the dose, virus strain, or host mouse strain, the outcome of infection can be inapparent infection, persistent infection, or death. The wealth ofmurine immunological reagents and inbred mouse strains, including immunodeficient mice, coupled with an easily manipulated virus causing several disease phenotypes, make MAV-1 an ideal model for studying viral pathogenesis in the natural host. This project will provide an understanding of (a) the role of the immune system in both control of viral infection and in producing viral disease, (b) the basis for infection by MAV-1 of two specific cell types, endothelial cells and macrophages, and (c) the contributions of early viral gene products to infection of cells in culture and mice. There are three specific aims: 1. Identify early immune response components affecting mouse susceptibility to infection. The role of B lymphocytes, natural killer cells, and monocytes/macrophages will be investigated using immunodeficient mice and depletions of specific cell types. 2. Determine whether MAV-1 infection induces gene expression changes that can alter effector function of endothelial and macrophage cells. Cellular genes, including interferon response, eytokine, and major histocompatibility complex gene class II genes will be characterized with respect to expression changes in target endothelial and macrophage cells by wild-type and early region 1A and 3 (E1A and E3) mutant viruses. The results of assays of in vitro and in vivo gene expression will be integrated to define host response pathways and strategies used by the virus to evade them. 3. Determine mechanisms by which viral early region genes contribute to MAV-1 infection. A biochemical assay will be used to identify host proteins that interact with MAV-1 E 1A and E3, and these results will be incorporated into models developed in Aim 2. Viruses with mutations in E1A, E1B, and E3 will be used to infect immunodeficient mice to test specific hypotheses about early adenoviral gene function in vivo. These studies will further our knowledge of adenovirus biology, host immune mechanisms and viral immune evasion.
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