Despite extensive structural, replicative, and genetic knowledge of adenoviruses and the different diseases produced by the 42 distinct types, little is known about the molecular mechanisms responsible for the pathogenesis of any of these diseases. The major goal of the proposed research is to use the cotton rat and mouse models previously described to investigate the molecular mechanism of the pathogenesis of adenovirus pneumonia. These studies will be directed toward determining: 1) the gene functions required to produce the pneumonia; 2) which early gene functions are expressed and in which cells other than the epithelial cells of the bronchi and bronchiols; 3) the specific cell types that compose the inflammatory response; 4) the specific role of the cytokines TNFalpha, IL- 1, and IL-6; 5) the role of cellular immunity and which viral antigens are required in the second phase of the pulmonary response, and 6) which gene(s) are critical to allow Ad7 to produce a much more severe pneumonia than Ad5, Ad11 to cause hemorrhagic cystitis, and Ad40 to induce severe infantile gastroenteritis. Studies will be done to determine whether the cytokine responses observed play a role in the pathogenesis of influenza A, poliomyelitis, and herpes simplex encephalitis.