One quarter of the world's population is infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Although most infected individuals successfully control or clear the infection, some individuals will progress to TB disease. Immune correlates identified using animal models are not always effectively translated to human TB, thus resulting in a slow pace of translational discoveries from animal models to human TB for many platforms including vaccines, therapeutics, biomarkers, and diagnostic discovery. Therefore, it is critical to improve our poor understanding of immune correlates of disease and protection that are shared across animal TB models and human TB. In this study, we have provided an in-depth identification of the conserved and diversified gene/immune pathways in TB models of nonhuman primate and diversity outbred mouse and human TB. Our results show that prominent differentially expressed genes/pathways induced during TB disease progression are conserved in genetically diverse mice, macaques, and humans. In addition, using gene-deficient inbred mouse models, we have addressed the functional role of individual genes comprising the gene signature of disease progression seen in humans with Mtb infection. We show that genes representing specific immune pathways can be protective, detrimental, or redundant in controlling Mtb infection and translate into identifying immune pathways that mediate TB immunopathology in humans. Together, our cross-species findings provide insights into modeling TB disease and the immunological basis of TB disease progression.

中文翻译：

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结核病和风险的免疫相关性在不同物种之间存在差异。


世界上四分之一的人口感染结核分枝杆菌 (Mtb)，它是结核病 (TB) 的病原体。尽管大多数感染者成功控制或清除了感染，但有些人仍会发展为结核病。使用动物模型识别的免疫相关因素并不总是能有效地转化为人类结核病，因此导致许多平台（包括疫苗、治疗方法、生物标志物和诊断发现）从动物模型到人类结核病的转化发现进展缓慢。因此，改善我们对动物结核病模型和人类结核病所共有的疾病和保护的免疫相关性的了解至关重要。在这项研究中，我们深入鉴定了非人灵长类动物结核病模型以及多样性远交小鼠和人类结核病模型中保守且多样化的基因/免疫途径。我们的结果表明，结核病进展期间诱导的显着差异表达基因/通路在遗传多样性的小鼠、猕猴和人类中是保守的。此外，使用基因缺陷的近交小鼠模型，我们已经解决了单个基因的功能作用，这些基因包括在结核分枝杆菌感染的人类中观察到的疾病进展的基因特征。我们表明，代表特定免疫途径的基因在控制结核分枝杆菌感染方面可能具有保护性、有害性或冗余性，并可转化为识别介导人类结核病免疫病理学的免疫途径。总之，我们的跨物种研究结果为结核病建模和结核病进展的免疫学基础提供了见解。