A Genetic Determinant of Resistance to HSV

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免疫反应，在决定对疱疹病毒感染的抵抗力方面发挥重要作用。对细胞、它们的相互作用、相对贡献和参与抗性的基因的定义对于设计增强对HSV-1的抵抗力的创新策略至关重要。我们在这里提出了一个控制HSV-1抗性的新基因座的证据。我们暂时命名为疱疹病毒耐药基因座(HRL)，它似乎与小鼠6号染色体上的肿瘤坏死因子P55受体(TNFR_1)紧密连锁。HRL是在研究过程中偶然发现的，以确定肿瘤坏死因子信号是否通过P55或p75(TNFR_2)或两者共同参与了对单纯疱疹病毒-L的保护作用。近交系小鼠HRL至少存在两个等位基因，C57BL/6和129品系分别存在一个抗性等位基因和一个易感等位基因。我们在一个N_2回交中确定，HRL是遗传的显性常染色体基因座，它只对雄性小鼠的抗性负责，而第二个被称为性别修饰基因座的基因座，SML，功能是增强雌性小鼠的抗性。除了确定对HSV攻击的抵抗力外，我们还提出了HRL也影响HSV重新激活的证据，可能是通过与另一个基因的相互作用(S)。未来对高密度脂蛋白的研究有可能揭示单纯疱疹病毒L感染的新治疗靶点，以及阻止或减少临床上重要的复发单纯疱疹病毒1型感染的新方法，例如疱疹间质角膜炎，这是发达国家的主要致盲原因。此外，HRL和SML的鉴定和表征有可能为基于性别的免疫差异提供重要的见解。因此，该建议的具体目的是(1)高分辨率地对HRL进行遗传定位，间隔1 cM；(2)鉴定一个B6衍生的细菌人工染色体(BAC)克隆，该克隆在129株或其他敏感株(如AJJ或DBA/2)的背景中以转基因形式表达时，能够显性地转移对HSV诱导的死亡的抗性；(3)利用生物信息学工具和其他方法来寻找拯救BAC中可能的HRL候选基因，并证明该基因在C57BL/6背景中的零突变对HSV敏感，从而确认该候选基因为HRL。

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.