A Genetic Determinant of Resistance to HSV

HSV 耐药性的遗传决定因素

• 批准号: 6778187
• 负责人: EDOUARD M CANTIN
• 金额: $ 43.75万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6778187
• 关键词: R factors; artificial chromosomes; biotechnology; gender difference; gene expression; genetic markers; genetic susceptibility; genetically modified animals; genotype; herpes simplex virus 1; immunity; immunogenetics; in situ hybridization; laboratory mouse; linkage mapping; molecular cloning; northern blottings; nucleic acid sequence; polymerase chain reaction; regulatory gene; virus diseases

DESCRIPTION (provided by applicant): Multiple genes, including both major histocompatability genes (H2) and non-H2 genes, play important roles in determining resistance to herpesvirus infections by regulating adaptive and innate immune responses, respectively. Definition of the cells, their interactions, relative contributions and genes involved in resistance is essential for the design of innovative strategies to augment resistance to HSV-1. We present here, evidence for a novel locus that governs resistance to HSV-1. The resistance locus that we have provisionally named Herpes Resistance Locus (Hrl) appears closely linked to the TNF p55 receptor (TNFR1) on murine chromosome 6. Hrl was discovered serendipitously in the course of studies to determine whether TNF signaling through the p55 or p75 (TNFR2) or both receptors, was involved in protection against HSV-l. There are at least two alleles for Hrl in inbred mouse strains, a resistance allele and a susceptibility allele present in C57BL/6 and 129 strains, respectively. We have determined in a N2 backcross that Hrl is inherited as dominant autosomal locus that is solely responsible for resistance in male mice, whereas a second locus termed the Sex Modifier Locus, Sml, functions to augment resistant in female mice. In addition to determining resistance to HSV challenge, we present evidence that Hrl also affects HSV reactivation, possibly through interaction with another gene(s). Future studies of Hrl have the potential to reveal new therapeutic targets for HSV-l infections and new approaches for blocking or reducing clinically important recurrent HSV-1 infections such as herpes stromal keratitis, a leading cause of blindness in developed countries. Moreover, the identification and characterization of both Hrl and Sml has the potential to provide important insights into sex-based differences in immunity. The specific aims of this proposal are therefore (1) to genetically map Hrl at high resolution to a 1 cM interval, (2) to identify a B6-derived bacterial artificial chromosome (BAC) clone that can dominantly transfer resistance to HSV induced mortality when expressed as a transgene in the 129 or other susceptible (e.g. AJJ or DBA/2) strain background and (3), to use bioinformatics tools and other approaches to identify possible candidate genes for Hrl in the rescuing BAC and demonstrate that null mutants of the gene in the C57BL/6 background are susceptible to HSV, thereby confirming the candidate gene as Hrl.

描述（由申请人提供）：多个基因，包括主要组织相容性基因（H2）和非H2基因，分别通过调节适应性和先天性免疫应答，在决定对疱疹病毒感染的抗性中发挥重要作用。细胞的定义，它们的相互作用，相对贡献和基因参与耐药性是至关重要的创新策略，以增加对HSV-1的耐药性的设计。我们在这里，一个新的基因座，控制HSV-1的耐药性的证据。我们暂时命名为疱疹抗性基因座（Hrl）的抗性基因座似乎与鼠6号染色体上的TNF p55受体（TNFR 1）紧密连锁。在研究过程中偶然发现了Hrl，以确定通过p55或p75（TNFR 2）或两种受体的TNF信号传导是否参与针对HSV-1的保护。在近交系小鼠品系中存在Hrl的至少两个等位基因，抗性等位基因和易感性等位基因分别存在于C57 BL/6和129品系中。我们已经在N2回交中确定，Hrl作为显性常染色体基因座遗传，其仅负责雄性小鼠中的抗性，而称为性别修饰基因座Sml的第二个基因座用于增强雌性小鼠中的抗性。除了确定对HSV攻击的抗性之外，我们还提供了Hrl也影响HSV再活化的证据，可能是通过与另一个基因的相互作用。Hrl的未来研究有可能揭示HSV-1感染的新治疗靶点和阻断或减少临床上重要的复发性HSV-1感染如疱疹性基质角膜炎（发达国家致盲的主要原因）的新方法。此外，Hrl和Sml两者的鉴定和表征具有提供对基于性别的免疫差异的重要见解的潜力。因此，该提议的具体目的是（1）以高分辨率将Hrl遗传作图至lcM间隔，（2）鉴定B6衍生的细菌人工染色体（BAC）克隆，其当在129个或其他易感的宿主细胞中表达为转基因时，可以显性地转移对HSV诱导的死亡率的抗性。（例如AJJ或DBA/2）菌株背景，和（3）使用生物信息学工具和其他方法来鉴定拯救BAC中Hrl的可能候选基因，并证明C57 BL/6背景中基因的无效突变体对HSV易感，从而确定候选基因为Hr 1。