A Genetic Determinant of Resistance to HSV

HSV 耐药性的遗传决定因素

• 批准号: 6927797
• 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/6927797
• 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，包括主要的组织相容性基因（H2）和非H2基因，分别通过调节适应性和先天免疫反应来确定对疱疹病毒感染的抗性发挥着重要作用。细胞的定义，它们的相互作用，相对贡献和抗药性涉及的基因对于设计创新策略以增强对HSV-1的抗性至关重要。我们在这里提出，证明了一个新型基因座，该基因座控制着对HSV-1的抵抗。我们临时命名的疱疹抗性基因座（HRL）的阻力基因座似乎与鼠染色体6的TNF p55受体（TNFR1）紧密相关。在研究过程中，偶然发现了HRL，以确定是否通过p55或P75（TNFR2）或两种受体来确定TNF信号传导。在近交小鼠菌株中，HRL至少有两个等位基因，一个抗性等位基因和C57BL/6和129菌株中存在的敏感性等位基因。我们已经在N2反向交叉中确定了HRL是遗传为主要的常染色体基因座，它完全负责雄性小鼠的耐药性，而第二个基因座则称为性修饰剂基因座，SML，功能在雌性小鼠中增强耐药性。除了确定对HSV挑战的抗性外，我们还提供了证据表明HRL还会影响HSV重新激活，这可能是通过与另一个基因的相互作用来影响。对HRL的未来研究有可能揭示有关HSV-L感染的新治疗靶标，以及阻止或减少临床上重要的复发性HSV-1感染的新方法，例如疱疹基质角膜炎，这是发达国家失明的主要原因。此外，HRL和SML的识别和表征都有潜力提供对基于性别的免疫差异的重要见解。因此，该提案的具体目的是（1）在高分辨率上以遗传映射到1 cm的间隔，（2），以识别B6衍生的细菌性人造染色体（BAC）克隆，可以在129或其他易于使用（例如，在129或其他易用的情况下用作传输时）对HSV诱导的死亡率显着转移耐药性（例如，例如AJJ），例如AJJ JJ或2BA，例如Ajj ajj或dbA，例如，ajj ajj或dba（例如，dba）/2BA/2BA（例如，DBA）/2BA/2BA（例如）/2BA/2BA/2BA/2BA/2BA（例如）/2BA/2BA/2BA/2BA/2BA/2BA/2BA/2BA/2BA/2BA/2BA/2BA（例如）/2BA/2BA（例如，DBA/2BA）。在拯救BAC中鉴定HRL可能候选基因的工具和其他方法，并证明C57BL/6背景中该基因的无效突变体对HSV敏感，从而证实了候选基因为HRL。