A Guinea Pig Model of Adenovirus Pneumonia

描述(申请人提供)：腺病毒(ADS)是儿童和成人中最常见的呼吸系统疾病的病原体之一，需要住院治疗，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在人类呼吸道疾病的病因学中发挥了重要作用，但人们对其独特病理生物学的分子基础知之甚少。由于缺乏可允许的Ad呼吸道感染动物模型，阻碍了对Ad相关严重呼吸道疾病常见并发症的分子机制的了解，如具有肺外临床表现的播散性感染和长期的肺部后遗症，并阻碍了全身抗病毒药物和其他治疗药物的体内测试。这项发展赠款申请将解决豚鼠腺病毒(GPAdV)感染其自然宿主Cavia porcellus作为哺乳动物腺病毒呼吸道感染的一种新的替代模型的特征。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病毒分离系统，它仍然是一种几乎没有特征的病毒。1.对GPAdV基因组进行测序和注释；2.建立检测GPAdV和滴定实验样本中感染性病毒载量的方法；3.描述GPAdV在其自然宿主猪仔体内呼吸道感染的基本特征。这项拟议的研究具有创新性，因为它首次检查了一种新的哺乳动物腺病毒，这种病毒在其自然宿主中引起急性呼吸道疾病，作为腺病毒致病的模型。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天地，并为实验动物这一重要感染源的诊断和治疗提供资源。公共卫生相关性：缺乏可允许的腺病毒呼吸道感染动物模型，阻碍了对腺病毒相关性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，并阻碍了体内抗病毒药物和其他治疗药物的测试。这项拟议的研究将利用豚鼠腺病毒(GPAdV)及其自然宿主豚鼠(Cavia Porcellus)建立允许的哺乳动物腺病毒肺炎模型，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的天地，并为诊断和管理生物医学研究中使用的实验室动物的一种普遍传染病提供资源。

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.