Host genetics plays an important role in determining the outcome of Mycobacterium tuberculosis infection. We previously found that Collaborative Cross (CC) mouse strains differ in their susceptibility to M. tuberculosis and that the CC042/GeniUnc (CC042) strain suffered from a rapidly progressive disease and failed to produce the protective cytokine gamma interferon (IFN-γ) in the lung. Here, we used parallel genetic and immunological approaches to investigate the basis of CC042 mouse susceptibility. Using a population derived from a CC001/Unc (CC001) × CC042 intercross, we mapped four quantitative trait loci (QTL) underlying tuberculosis immunophenotypes (Tip1 to Tip4). These included QTL that were associated with bacterial burden, IFN-γ production following infection, and an IFN-γ-independent mechanism of bacterial control. Further immunological characterization revealed that CC042 animals recruited relatively few antigen-specific T cells to the lung and that these T cells failed to express the integrin alpha L (αL; i.e., CD11a), which contributes to T cell activation and migration. These defects could be explained by a CC042 private variant in the Itgal gene, which encodes CD11a and is found within the Tip2 interval. This 15-bp deletion leads to aberrant mRNA splicing and is predicted to result in a truncated protein product. The ItgalCC042 genotype was associated with all measured disease traits, indicating that this variant is a major determinant of susceptibility in CC042 mice. The combined effect of functionally distinct Tip variants likely explains the profound susceptibility of CC042 mice and highlights the multigenic nature of tuberculosis control in the Collaborative Cross.IMPORTANCE The variable outcome of Mycobacterium tuberculosis infection observed in natural populations is difficult to model in genetically homogeneous small-animal models. The newly developed Collaborative Cross (CC) represents a reproducible panel of genetically diverse mice that display a broad range of phenotypic responses to infection. We explored the genetic basis of this variation, focusing on a CC line that is highly susceptible to M. tuberculosis infection. This study identified multiple quantitative trait loci associated with bacterial control and cytokine production, including one that is caused by a novel loss-of-function mutation in the Itgal gene, which is necessary for T cell recruitment to the infected lung. These studies verify the multigenic control of mycobacterial disease in the CC panel, identify genetic loci controlling diverse aspects of pathogenesis, and highlight the utility of the CC resource.

中文翻译：

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功能上重叠的变体可控制协作型交叉小鼠中的肺结核易感性。

宿主遗传学在确定结核分枝杆菌感染的结果中起重要作用。我们先前发现，协作十字（CC）小鼠品系对结核分枝杆菌的敏感性不同，并且CC042 / GeniUnc（CC042）品系患有快速进行性疾病，并且未能在小鼠中产生保护性细胞因子γ干扰素（IFN-γ）。肺。在这里，我们使用了并行的遗传和免疫学方法来研究CC042小鼠易感性的基础。使用从CC001 / Unc（CC001）×CC042交配得到的种群，我们绘制了结核免疫表型（Tip1至Tip4）的四个定量性状位点（QTL）。这些包括与细菌负荷，感染后IFN-γ产生以及细菌控制的IFN-γ独立机制有关的QTL。进一步的免疫学特征表明，CC042动物向肺部募集了相对较少的抗原特异性T细胞，并且这些T细胞未能表达整联蛋白αL（αL；即CD11a），这有助于T细胞的活化和迁移。这些缺陷可以通过Itgal基因中的CC042私人变体解释，该变体编码CD11a，在Tip2区间内发现。这种15 bp的缺失会导致异常的mRNA剪接，并预计会导致蛋白质产物被截断。ItgalCC042基因型与所有测得的疾病特征相关，表明该变体是CC042小鼠易感性的主要决定因素。功能上不同的Tip变体的综合作用可能解释了CC042小鼠的深远敏感性，并突出了协作型交叉中结核病控制的多基因性质。重要信息在自然群体中观察到的结核分枝杆菌感染的可变结果很难在小规模的遗传同质模型中模拟。动物模型。新开发的协作十字（CC）代表了一组可复制的遗传多样性小鼠，这些小鼠表现出对感染的广泛表型反应。我们探索了这种变异的遗传基础，重点研究了高度易受结核分枝杆菌感染的CC品系。这项研究确定了与细菌控制和细胞因子产生相关的多个定量性状基因座，包括由Itgal基因中新的功能丧失突变引起的突变，这是T细胞募集到感染肺部所必需的。这些研究验证了CC小组对分枝杆菌疾病的多基因控制，确定了控制发病机理各个方面的遗传基因座，并强调了CC资源的实用性。