A Genetic Determinant of Resistance to HSV

HSV 耐药性的遗传决定因素

• 批准号: 6543198
• 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/6543198
• 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）：多种基因，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免疫反应在决定对疱疹病毒感染的抗性中发挥重要作用。定义细胞、它们之间的相互作用、相对贡献和参与耐药性的基因对于设计创新策略以增强对HSV-1的耐药性至关重要。我们在这里提出了一个新的基因座控制对HSV-1的抗性的证据。我们暂时命名为疱疹抗性位点（Hrl）的耐药位点似乎与小鼠6号染色体上的TNF p55受体（TNFR1）密切相关。Hrl是在研究过程中偶然发现的，以确定TNF信号是否通过p55或p75 （TNFR2）或两个受体参与对hsv - 1的保护。在自交系小鼠中存在至少2个Hrl等位基因，分别在C57BL/6和129株中存在抗性等位基因和易感等位基因。我们在N2回交中确定，Hrl作为显性常染色体位点遗传，仅负责雄性小鼠的抗性，而第二个位点称为性别修饰位点Sml，在雌性小鼠中起增强抗性的作用。除了决定对HSV的抵抗，我们提出的证据表明，Hrl也影响HSV的再激活，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，以及阻断或减少临床上重要的复发性HSV-1感染的新方法，如疱疹间质角膜炎，这是发达国家失明的主要原因。此外，Hrl和Sml的鉴定和表征有可能为了解基于性别的免疫差异提供重要见解。因此，本提案的具体目标是：(1)以高分辨率绘制Hrl在1 cM间隔内的遗传图谱；(2)鉴定b6衍生的细菌人工染色体（BAC）克隆，该克隆在129或其他易感菌株（如AJJ或DBA/2）背景中作为转基因表达时，可以主要转移对HSV诱导死亡的抗性；利用生物信息学工具和其他方法鉴定挽救性BAC中Hrl的可能候选基因，并证明C57BL/6背景中该基因的零突变体对HSV易感，从而确认候选基因为Hrl。