Genetics of Host Resistance & Susceptibility to TB

描述（由申请人提供）：免疫活性个体对结核病易感性的显著差异部分可由宿主群体内的遗传异质性解释。然而，抗结核免疫的遗传控制的精确机制是未知的。我们采用结核病小鼠实验模型，对免疫活性近交系小鼠品系中结核病抗性的自然发生变异进行遗传分析，以鉴定和分离对确定这种感染易感性重要的基因。我们先前已经定位了sstl基因座，它控制肺结核感染后早期的进展。使用sst 1抗性同源小鼠，我们绘制了6个新的数量性状基因座（QTL），控制结核病抗性之间的sst 1抗性主机的变化。这些基因座中的一些基因座的功能表达是ssl依赖的。我们将研究新的位点，并利用基因型辅助育种和先进的回交-互交后代测试来表征它们可能的相互作用，以缩小候选区间并为其进一步的遗传解剖建立条件。我们将通过在C3 H背景上转移新的候选QTL来产生一组同源菌株，并将这些位点解剖成更小的染色体片段以便于定位克隆。利用新的同类菌株，我们将研究在耐药和易感动物中形成肺肉芽肿的细胞。在分子水平上确定结核病耐药和易感性的相关性，并为每个位点建立替代表型，这些表型可用作预测分离人群中遗传易感性的替代生物标志物。QTL编码的分子的鉴定将有助于解释在系统和肺特异性水平上宿主对结核病的抗性机制的遗传多态性所赋予的关键功能差异。

DESCRIPTION (provided by applicant): A significant variation in susceptibility to tuberculosis among immunocompetent individuals is partially explained by genetic heterogeneity within the host population. However, precise mechanisms of the genetic control of anti-tuberculosis immunity are unknown. We employ a mouse experimental model of tuberculosis for the genetic analysis of the naturally occurring variation in tuberculosis resistance among immunocompetent inbred mouse strains to identify and isolate genes important for determining susceptibility to this infection. We have previously mapped the sstl locus, which controls progression of pulmonary tuberculosis early after infection. Using the sst1-resistant congenic mice we mapped six new quantitative trait loci (QTL) that control variation in tuberculosis resistance among the sstl-resistant hosts. Functional expression of some of those loci is sstl-dependent. We will study the new loci and characterize their possible interactions using genotype-assisted breeding and advanced backcross-intercross progeny testing in order to narrow candidate intervals and establish conditions for their further genetic dissection. We will generate a set of congenic strains by transferring new candidate QTLs on a C3H background and dissect those loci into smaller chromosomal segments to facilitate positional cloning. Using new congenic strains we will study cells that form lung granulomas in resistant and susceptible animals. Identify correlates of tuberculosis resistance and susceptibility at molecular level and establish proxy phenotypes for each locus that can be used as surrogate biomarkers for predicting genetic susceptibility in segregating populations. Identification of molecules encoded in QTLs will help explain critical functional differences conferred by the genetic polymorphisms on mechanisms of host resistance to tuberculosis at both systemic and lung-specific levels.