New locus controlling suscept. to TB: genetics & funct.

描述（由申请人提供）：预计总共 225 1998 年至 2030 年间，将出现 100 万新发结核病病例。结果 结核分枝杆菌 (MTB) 原发感染的比例各不相同，并且 免疫能力强的宿主，仅产生 10% 的终生患病风险 临床疾病。结核病易感性的显着差异 免疫功能正常的个体之间的这种现象仍然无法解释。差异在于 类似危险因素下结核感染的结果 支持宿主遗传背景在易感性中发挥重要作用 向临床疾病进展。因此，遗传鉴定 与结核病易感性相关的因素具有重要意义 对控制疾病的影响。 我们使用 MTB 强毒株感染的小鼠实验模型来 表征负责控制结核感染的基因 在免疫功能正常的宿主中。我们已确定并映射到 2 cM 间隔 小鼠 1 号染色体上的一个新位点 (sst1) 对 控制主要在肺部的有毒 MTB 的生长。对其的观察 表型表达表明控制感染的遗传机制 携带强毒力 MTB 的疫苗与控制无毒疫苗的疫苗不同 牛分枝杆菌卡介苗菌株。产生了一组 sst1 同类自交系 小鼠，我们建议使用它们 (1) 来分离 sst1 候选基因 定位克隆； (2) 鉴定负责的遗传多态性 结核病易感性； (3)识别细胞和功能通路 受 sst1 多态性影响。 拟议项目将确定该药物的性质和作用机制 小鼠体内的 sst1，将来应该可以分离出它的人类 同源物及其在结核病易感性中的作用分析 人类。了解遗传决定的运作机制 在肺部结核感染过程中会提供新的 深入了解结核病的发病机制并提出改进策略 用于治疗和预防疾病。

DESCRIPTION (provided by the applicant): It is projected that a total of 225 million new cases of tuberculosis will occur between 1998 and 2030. The outcome of primary infection with Mycobacterium tuberculosis (MTB) varies and, in immunocompetent hosts, imparts only a 10 percent lifetime risk of developing clinical disease. The significant variation in tuberculosis susceptibility among immunocompetent individuals remains unexplained. Differences in the outcome of tuberculosis infection in the setting of similar risk factors support a significant role of the host genetic background in predisposition to progression towards clinical disease. Therefore, identification of genetic factors associated with susceptibility to tuberculosis will have important implications for controlling the disease. We use a mouse experimental model of infection with virulent strain of MTB to characterize genes that are responsible for control of tuberculosis infection in immunocompetent hosts. We have identified and mapped to a 2 cM interval on mouse chromosome 1 a novel locus (sst1) that significantly contributes to control of growth of virulent MTB primarily in the lungs. Observations on its phenotypic expression demonstrate that genetic mechanisms controlling infection with virulent MTB are distinct from those that control an avirulent vaccine strain of M bovis BCG. Having generated a set of sst1-congenic inbred strains of mice, we propose to use them (1) to isolate the sst1-candidate genes by positional cloning; (2) to identify genetic polymorphism responsible for tuberculosis susceptibility; (3) to identify cells and functional pathways affected by the sst1 polymorphism. The proposed project will identify the nature and mechanism of action of the sst1 in mice, which in the future should permit isolation of its human homologue and the analysis of its role in tuberculosis susceptibility in humans. The understanding of genetically determined mechanisms that operate during the course of tuberculosis infection in the lung will provide new insights into the pathogenesis of tuberculosis and suggest improved strategies for treatment and prevention of the disease.