Genetic Variability and Virulence of Human Adenovirus 7

描述（由申请方提供）：7型腺病毒（Ad7）是一种重要的人类病原体，与新兵中严重和致命的儿科急性肺部感染和呼吸道疾病暴发相关。迄今为止描述的超过15种基因组类型的广泛遗传变异性是该腺病毒血清型的特征。在明确定义的地理区域中，对与呼吸道疾病相关的Ad7基因变异的研究表明，只有少数密切相关的基因组类型在循环，并且一种DNA变体在取代另一种之后的较长时间内变得普遍。新的Ad7基因组类型在特定地理区域的出现通常与严重呼吸道疾病的爆发有关，这表明Ad7基因组变体之间存在致病潜力的差异。然而，这些基因组类型替换或移位的分子基础是未知的。关于自然界中遗传变异对腺病毒毒力的相对影响的知识仍然存在严重的空白。此外，与其他腺病毒血清型相比，Ad7的明显更高致病性的实际决定因素尚未明确确定。该提案旨在比较两种流行的Ad7基因组类型的遗传组成和临床相关表型，这两种基因组类型构成了自然界中有据可查的基因组类型转变的许多例子之一：7c和7h。核心假设是，在给定的地理区域中，人类Ad 7的进化至少部分地由作用于DNA变体的免疫应答的选择性压力驱动，所述DNA变体在编码免疫调节功能的区域处的遗传组成不同。特异性目的1将决定编码免疫调节产物E1和E3的病毒基因组早期区域的遗传变异程度。具体目标2将通过检查a）肺上皮细胞中的病毒复制，B）对抗病毒细胞因子的抗性，c）肺内感染后小鼠肺中诱导的急性炎症反应和d）通过病毒型特异性多克隆兔抗血清中和病毒感染性，比较反映病毒适应性、传播性、毒力和免疫逃避潜力的表型。这些研究将提供深入了解的分子机制的主要毒力的Ad株的出现，并将有助于确定候选人的致病性和健身的人腺病毒7型的决定因素。

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.