Host Determinants of Tuberculosis Susceptibility

项目1：结核病易感性的宿主决定因素 翻译后摘要：结核分枝杆菌（Mtb）感染的结果是非常 多样化。许多受感染的人没有疾病的迹象。其中， 当患者患病时，病理的时间、位置和严重程度是显著可变的。 宿主种群中的遗传多样性是造成这种变异的主要因素， 负责的等位基因和机制定义不清， 实验性地解决。在这个项目中，我们通过以下方式来解决这个固有的复杂问题： 利用高度遗传多样性，但精确遗传的 定义，小组的重组近交系小鼠被称为协作交叉。的 该群体的独特结构允许连续评估可变性状， 反映了发病机制的不同方面。我们利用了这种迭代表型分析 在多个层面剖析结核病易感性的遗传基础的战略。这些现有 研究表明，Kit配体（KitL）变异是结核病的重要决定因素 在小鼠和人类中，表明病原体和宿主之间的遗传相互作用 是检测改变疾病进展的新基因的敏感指标， 强调了使用离体系统来剖析结核分枝杆菌之间相互作用的能力， 和巨噬细胞。在建议的计划中，我们会继续进行这些工作， 战略： 目的1：研究结核病易感性与KitL基因连锁的机制。 老鼠和人类 目的2：利用小鼠和细菌遗传学的组合技术研究宿主-病原体 基因相互作用 目的3：利用CC板来剖析结核分枝杆菌-巨噬细胞相互作用。 结合起来，这些新的资源和方法有望从根本上提供 宿主和细菌遗传变异对结核分枝杆菌结果作用的新认识 感染 !

Project 1: Host Determinants of TB Susceptility Abstract: The outcomes of Mycobacterium tuberculosis (Mtb) infections are extremely diverse. Many infected individuals show no signs of disease. Among those that do become ill, the timing, location, and severity of pathology are remarkably variable. Genetic diversity in the host population is a major contributor to this variability, but the responsible alleles and mechanisms are poorly defined and have been difficult to address experimentally. In this project, we approach this inherently complex problem by modeling host diversity using a highly genetically diverse, but precisely genetically defined, panel of recombinant inbred mice known as the Collaborative Cross. The unique structure of this population allows the sequential evaluation of variable traits that reflect distinct aspects of pathogenesis. We took advantage of this iterative-phenotyping strategy to dissect the genetic basis of TB susceptibility at multiple levels. These prior studies implicated Kit Ligand (KitL) variation as an important determinant of TB disease in mice and humans, suggested that genetic interactions between pathogen and host are a sensitive metric for detecting new genes that alter disease progression, and highlighted the power of using ex vivo systems to dissect the interaction between Mtb and the macrophage. In the proposed project, we will continue to pursue these strategies to: Aim 1: Investigate the mechanism of KitL-linked susceptibility to TB disease in mice and humans. Aim 2: Use combinatorial mouse and bacterial genetics to dissect host-pathogen genetic interactions. Aim 3: Exploit the CC panel to dissect the Mtb-macrophage interaction. In combination, these new resources and approaches promise to provide fundamentally new insight into the role of host and bacterial genetic variation on the outcome of Mtb infection. !