Genetics of Host Resistance & Susceptibility to TB

描述（由申请人提供）：免疫能力强的个体对结核病易感性的显著差异部分可以通过宿主群体内的遗传异质性来解释。然而，基因控制抗结核免疫的确切机制尚不清楚。我们采用小鼠结核病实验模型，对具有免疫能力的近交系小鼠自然发生的结核病耐药性变异进行遗传分析，以鉴定和分离确定对这种感染易感性的重要基因。我们之前已经绘制了sstl位点，它在感染后早期控制肺结核的进展。利用sst1抗性基因小鼠，我们绘制了6个新的控制sst1抗性宿主间结核抗性变异的数量性状位点（QTL）。其中一些位点的功能表达仍然是依赖的。我们将利用基因型辅助育种和先进的回交杂交后代测试来研究新的基因座，并表征它们可能的相互作用，以缩小候选间隔，并为进一步的遗传解剖建立条件。我们将通过在C3H背景上转移新的候选qtl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。使用新的同源菌株，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因素，并为每个位点建立代理表型，这些表型可作为预测分离群体遗传易感性的替代生物标志物。鉴定编码在qtl中的分子将有助于解释宿主在全身和肺特异性水平上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.