General Summary Adenoviruses (Ads) are among the most prevalent causative agents of respiratory disease requiring hospitalization in both children and adults, and have been widely recognized as important opportunistic pathogens for immunocompromised patients. Despite the important role of Ads in the etiology of human respiratory disease, relatively little is known about the molecular bases of their unique pathobiology. The lack of a permissive animal model of Ad respiratory infection has hampered the understanding of the molecular mechanisms underlying the frequently observed complications of Ad-associated severe respiratory illness such as disseminated infection with extrapulmonary clinical manifestations, and long-term pulmonary sequelae, and has precluded the testing of systemic antivirals and other therapeutic agents in vivo. This developmental grant application will address the characterization of guinea pig adenovirus (GPAdV) infection of its natural host, Cavia porcellus, as a novel surrogate model of mammalian adenovirus respiratory infection. GPAdV is a natural respiratory pathogen of guinea pigs but remains a virtually uncharacterized virus due to the lack of suitable in vitro systems for viral isolation. Three specific aims will be pursued: 1: To sequence and annotate the genome of GPAdV, 2: To develop assays for the detection of GPAdV and titration of infectious virus load in experimental samples, and 3: To delineate the basic characteristics of GPAdV respiratory infection in its natural host, Cavia porcellus. The proposed research is innovative because it examines for the first time a new mammalian adenovirus that causes acute respiratory disease in its natural host as a model of adenovirus pathogenesis. These studies will break new ground toward the understanding of the pathobiology of mammalian adenovirus respiratory infections, and provide resources for the diagnosis and management of an important infectious agent of laboratory animals. PUBLIC HEALTH RELEVANCE: The lack of a permissive animal model of adenovirus respiratory infection has hampered the understanding of the mechanisms and virus-host interactions underlying the frequently observed complications of adenovirus- associated severe respiratory illness, and has precluded the testing of antivirals and other therapeutic agents in vivo. The proposed study will develop a permissive mammalian model of adenovirus pneumonia using guinea pig adenovirus (GPAdV) and its natural host, Cavia porcellus, and will thus provide a new resource for design and testing of intervention strategies. In addition, these studies will break new ground toward the understanding of the pathobiology of mammalian adenovirus respiratory infections, and generate resources for the diagnosis and management of a prevalent infectious agent of laboratory animals used in biomedical research.