Genetic Variability and Virulence of Human Adenovirus 7

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DESCRIPTION (provided by applicant): Adenovirus type 7 (Ad7) is an important human pathogen associated with severe and fatal pediatric acute pulmonary infection and outbreaks of respiratory illness among military recruits. Extensive genetic variability with more than 15 genome types described to date is a characteristic of this adenovirus serotype. Studies of genetic variation of Ad7 associated with respiratory disease in well-defined geographic areas have shown that only a few closely related genome types circulate and that one DNA variant becomes prevalent over extended periods of time after substituting for another. The emergence of novel Ad7 genome types in a given geographic area is often associated with outbreaks of severe respiratory illness, suggesting the existence of differences in pathogenic potential among Ad7 genomic variants. However, the molecular bases of these genome type substitutions or shifts are unknown. There is still a critical gap in the knowledge about the relative impact of genetic variation in nature on adenovirus virulence. Moreover, the actual determinants of the apparent higher pathogenicity of Ad7 as compared to other adenovirus serotypes have not been clearly identified. This proposal seeks to compare the genetic make up and clinically relevant phenotypes of two prevalent Ad7 genome types that constitute one of the many examples of well documented genome type shifts in nature: 7c and 7h. The central hypothesis is that the evolution of human Ad 7 in a given geographic area is driven at least in part by the selective pressure of the immune response acting upon DNA variants that differ in their genetic makeup at regions encoding immunomodulatory functions. Specific Aim 1 will determine the extent of genetic variability in the early regions of the viral genome encoding immunomodulatory products, E1 and E3. Specific Aim 2 will compare phenotypes reflecting viral fitness, transmissibility, virulence and potential for immune evasion by examining a) viral replication in lung epithelial cells, b) resistance to antiviral cytokines, c) the acute inflammatory response induced in the mouse lung after intratracheal infection and d) neutralization of viral infectivity by serotype-specific polyclonal rabbit antisera. These studies will provide insight into the molecular mechanisms underlying the emergence of predominant virulent Ad strains and will help identify candidate determinants of pathogenicity and fitness of human adenovirus type 7.