A Guinea Pig Model of Adenovirus Pneumonia

腺病毒（Ads）是儿童和成人需要住院治疗的呼吸系统疾病中最常见的病原体之一，并且已被广泛认为是免疫功能低下患者的重要机会性病原体。尽管Ads在人类呼吸系统疾病的病因学中起着重要作用，但对其独特病理生物学的分子基础知之甚少。Ad呼吸道感染动物模型的缺乏阻碍了对Ad相关严重呼吸道疾病常见并发症（如伴有肺外临床表现的播散性感染和长期肺部后遗症）的分子机制的理解，也阻碍了体内系统抗病毒药物和其他治疗药物的测试。本研究将研究豚鼠腺病毒（GPAdV）感染其天然宿主porcellus Cavia的特性，并将其作为哺乳动物腺病毒呼吸道感染的新替代模型。GPAdV是豚鼠的一种天然呼吸道病原体，但由于缺乏合适的体外系统进行病毒分离，它实际上仍然是一种未表征的病毒。研究将有三个具体目标：1 .对GPAdV的基因组进行测序和注释；2 .开发实验样品中GPAdV的检测和感染病毒载量的测定方法；3 .描述GPAdV在其天然宿主porcellus Cavia呼吸道感染的基本特征。这项拟议的研究具有创新性，因为它首次研究了一种新的哺乳动物腺病毒，它可以在其自然宿主中引起急性呼吸道疾病，作为腺病毒发病机制的模型。这些研究将为理解哺乳动物腺病毒呼吸道感染的病理生物学开辟新的领域，并为实验室动物的一种重要感染源的诊断和管理提供资源。公共卫生相关性：腺病毒呼吸道感染动物模型的缺乏阻碍了对腺病毒相关严重呼吸道疾病常见并发症的机制和病毒-宿主相互作用的理解，并阻碍了抗病毒药物和其他治疗药物的体内测试。本研究将利用豚鼠腺病毒（GPAdV）及其天然宿主Cavia porcellus建立腺病毒肺炎的允许哺乳动物模型，从而为干预策略的设计和测试提供新的资源。此外，这些研究将为理解哺乳动物腺病毒呼吸道感染的病理生物学开辟新天地，并为生物医学研究中使用的实验动物普遍感染源的诊断和管理提供资源。

DESCRIPTION (provided by applicant): 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.