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: 6777938
• 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 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6777938
• 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，与军队新兵中严重和致命的儿科急性肺部感染和呼吸道疾病的爆发有关。这种腺病毒血清型的特点是广泛的遗传变异，迄今已描述的基因组类型超过15种。在明确的地理区域，对与呼吸系统疾病相关的Ad7遗传变异的研究表明，只有少数密切相关的基因组类型循环，一种DNA变体在取代另一种DNA变体后，在较长时间内变得普遍。在特定地理区域出现新的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。在自然界遗传变异对腺病毒毒力的相对影响的知识方面，仍然存在一个关键的差距。此外，与其他腺病毒血清型相比，Ad7明显更高的致病性的实际决定因素尚未明确确定。本研究旨在比较两种常见的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充分记录的基因组类型转移的许多例子之一：7c和7h。核心假设是，在特定地理区域，人类Ad - 7的进化至少部分是由免疫反应的选择性压力驱动的，这些压力作用于编码免疫调节功能区域的DNA变异，这些变异在基因组成上存在差异。特异性目标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)病毒在肺上皮细胞中的复制，b)对抗病毒细胞因子的抗性，c)气管内感染后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对病毒感染性的中和，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显性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。