Genetic Variability and Virulence of Human Adenovirus 7

人腺病毒 7 号的遗传变异和毒力

• 批准号: 6887743
• 负责人: Adriana Elisa Kajon
• 金额: $ 10万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6887743
• 关键词: Adenoviridae; clinical research; enzyme linked immunosorbent assay; genetic strain; genetic susceptibility; genome; host organism interaction; human tissue; immune response; immunogenetics; immunomodulators; inflammation; interferons; laboratory mouse; nucleic acid sequence; pathologic process; phenotype; polymerase chain reaction; respiratory epithelium; respiratory infections; tumor necrosis factor alpha; virulence; virus genetics; virus infection mechanism; virus replication

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.

描述（由申请人提供）：7 型腺病毒 (Ad7) 是一种重要的人类病原体，与严重和致命的小儿急性肺部感染以及新兵呼吸道疾病的爆发有关。迄今为止已描述的超过 15 种基因组类型的广泛遗传变异性是该腺病毒血清型的一个特征。对特定地理区域内与呼吸道疾病相关的 Ad7 遗传变异的研究表明，只有少数密切相关的基因组类型在传播，并且一种 DNA 变异在替代另一种 DNA 变异后会在很长一段时间内流行。特定地理区域中新 Ad7 基因组类型的出现通常与严重呼吸道疾病的爆发有关，这表明 Ad7 基因组变异之间存在致病潜力差异。然而，这些基因组类型取代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的认识仍然存在重大差距。此外，与其他腺病毒血清型相比，Ad7 明显较高致病性的实际决定因素尚未明确。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，这两种类型构成了自然界中有据可查的基因组类型转变的众多例子之一：7c 和 7h。中心假设是，人类 Ad 7 在特定地理区域的进化至少部分是由作用于 DNA 变体的免疫反应的选择性压力驱动的，这些 DNA 变体在编码免疫调节功能的区域的基因组成不同。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。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抵抗力，c) 气管内感染后在小鼠肺部诱导的急性炎症反应，以及 d) 血清型特异性多克隆兔抗血清中和病毒感染性，来比较反映病毒适应性、传播性、毒力和免疫逃避潜力的表型。这些研究将深入了解主要毒力Ad毒株出现的分子机制，并将有助于确定人类7型腺病毒致病性和适应性的候选决定因素。