Genetic Variability and Virulence of Human Adenovirus 7

描述(申请人提供)：7型腺病毒(Ad7)是一种重要的人类病原体，与严重和致命的儿科急性肺部感染和新兵呼吸系统疾病的爆发有关。迄今为止所描述的15种基因组类型的广泛遗传变异是该腺病毒血清型的一个特征。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中，并且一种DNA变体在替代另一种之后会在较长的一段时间内流行。在特定的地理区域出现新的Ad7基因组类型通常与严重呼吸系统疾病的爆发有关，这表明Ad7基因组变异之间存在致病潜力的差异。然而，这些基因组类型替换或转变的分子基础尚不清楚。关于自然界遗传变异对腺病毒毒力的相对影响，目前仍存在严重的知识差距。此外，与其他腺病毒血清型相比，Ad7致病性明显更高的实际决定因素还没有明确确定。这项建议试图比较两种流行的Ad7基因组类型的遗传组成和临床相关的表型，这两种类型构成了自然界中许多有充分证据的基因组类型转变的例子之一：7C和7H。中心假设是，人类Ad7在特定地理区域的进化至少部分是由免疫反应的选择性压力驱动的，这些免疫反应作用于DNA变体，这些DNA变体在编码免疫调节功能的区域具有不同的遗传组成。具体目标1将确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。特异性目标2将通过检测a)肺上皮细胞中的病毒复制，b)对抗病毒细胞因子的抵抗力，c)气管内感染后小鼠肺内诱导的急性炎症反应，以及d)血清特异性多克隆兔抗血清中和病毒感染性，比较反映病毒适合性、传播性、毒力和免疫逃避潜力的表型。这些研究将有助于深入了解主要毒力Ad株出现的分子机制，并有助于确定人腺病毒7型致病性和适合性的候选决定因素。

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.