Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States.
Department of Molecular Genetics and Microbiology, Duke University, Durham, United States.
Elife. 2022 Feb 3;11:e74419. doi: 10.7554/eLife.74419.
The outcome of an encounter with () depends on the pathogen's ability to adapt to the variable immune pressures exerted by the host. Understanding this interplay has proven difficult, largely because experimentally tractable animal models do not recapitulate the heterogeneity of tuberculosis disease. We leveraged the genetically diverse Collaborative Cross (CC) mouse panel in conjunction with a library of mutants to create a resource for associating bacterial genetic requirements with host genetics and immunity. We report that CC strains vary dramatically in their susceptibility to infection and produce qualitatively distinct immune states. Global analysis of transposon mutant fitness (TnSeq) across the CC panel revealed that many virulence pathways are only required in specific host microenvironments, identifying a large fraction of the pathogen's genome that has been maintained to ensure fitness in a diverse population. Both immunological and bacterial traits can be associated with genetic variants distributed across the mouse genome, making the CC a unique population for identifying specific host-pathogen genetic interactions that influence pathogenesis.
与 () 的遭遇结果取决于病原体适应宿主施加的可变免疫压力的能力。事实证明，理解这种相互作用具有一定难度，这主要是因为实验上易于处理的动物模型不能重现结核病疾病的异质性。我们利用遗传多样性的合作交叉（CC）小鼠品系，结合突变体文库，创建了一个资源，用于将细菌遗传要求与宿主遗传学和免疫联系起来。我们报告称，CC 品系在感染易感性方面差异巨大，并产生了定性不同的免疫状态。对 CC 品系中转座子突变体适应性（TnSeq）的全球分析表明，许多毒力途径仅在特定的宿主微环境中需要，这确定了病原体基因组的很大一部分，这些部分得以保留是为了确保在多样化的种群中具有适应性。免疫和细菌特征都可以与分布在整个小鼠基因组上的遗传变异相关联，这使得 CC 成为一个独特的群体，可用于鉴定影响发病机制的特定宿主-病原体遗传相互作用。
