Immune Determinants of the Course of Mycobacterium tuberculosis infection and Disease

摘要-项目2与结核分枝杆菌(结核分枝杆菌)初次相遇 肺泡巨噬细胞(AM)与活动性疾病的发展是一个连续体，在这个连续体中，无症状 感染可能在较长时间内发展为结核病(TB)。主机回应说 必须随着感染的进展而演变为疾病还没有定义。同样不清楚的是， 结核分枝杆菌-调节宿主反应的内在因素，因此，结核分枝杆菌进展的动力学 传染给疾病。我们已经确定了一个生物标记物的特征(PREDICT29)，它可以预测 感染进展的风险。临床流行病学研究发现两类结核分枝杆菌 从指示病例传播的杆菌在家庭接触者中引起感染的能力 (HHC)：MTB-HT(高传输)和Mtb-LT(低传输)。显示Mtb-HTIC的胸部X光 空洞病的发生频率增加。C3HeB/FEJ小鼠Mtb-HT和Mtb-LT分析显示 两株病毒在1)AM的反应；2)免疫病理方面有显著差异 模式，只有在结核杆菌-羟色胺感染的小鼠才有明显的肺坏死性损害；iii)T细胞在 感染的慢性期；以及iv)结核分枝杆菌细胞-的表达 包膜脂类。因此，Mtb-HT和Mtb-LT的这些特征可能将Mtb的内在因素与差异联系在一起 调节早期先天免疫反应(结核分枝杆菌-AM相互作用)，导致发展 独特的适应性免疫，进而控制无症状的动力学和频率 感染会发展成疾病。PREDICT29(区分进行项与非进行项)，in 结合ACS-COR签名(标识感染的较后阶段的个体)， 能够将受试者安置在我们的队列中，在早期阶段感染Mtb-HT和Mtb-LT 指感染的进展期或非进展期或感染的晚期。一种体外实验的组合 细胞系统、单细胞rna-seq分析、高维质量细胞术和纳米串技术 将被用来表征这些不同亚群所表现出的免疫反应。我们建议 为了检验以下假设：i)Mtb-HT和Mtb-LT诱导不同的AM反应；ii)不同的T细胞和 Mtb-HT和Mtb-LT感染HHC的抗体应答差异调节 免疫病理学和疾病进展；iii)记忆T细胞在调节感染中发挥作用 进步。Mtb-HT和Mtb-LT亚群感染的免疫学分析 受试者在感染的特定阶段，重点是早期结核分枝杆菌与AM的相互作用，适应性T细胞和 抗体反应，将提供大量信息，将阐明 在进展者和非进展者以及结核分枝杆菌的背景下调节感染和疾病结局- 内在因素。

ABSTRACT - PROJECT 2 Between the initial encounter of Mycobacterium tuberculosis (Mtb) with alveolar macrophages (AM) and the development of active disease lies a continuum in which asymptomatic infection may progress to tuberculosis (TB) disease over an extended timeframe. The host response that must evolve as the infection progresses toward disease has not been defined. Equally unclear is the role of Mtb-intrinsic factors in modulating the host response and consequently, the kinetics of the progression of infection to disease. We have characterized a biomarker signature (PREDICT29) that can predict the risks for progression from infection. Clinical epidemiological study identified 2 classes of Mtb based on the capacity of the bacilli from index cases to be transmitted to cause infection in household contacts (HHC): Mtb-HT (high transmission) and Mtb-LT (low transmission). Chest x-ray of Mtb-HT IC displayed increased frequency of cavitary disease. Analysis of Mtb-HT and Mtb-LT in C3HeB/FeJ mice revealed remarkable differences among the 2 strains in i) the responses elicited in AM; ii) the immunopathological patterns, with lung necrotic lesions only apparent in Mtb-HT infected mice; iii) the T cell response during the chronic phase of infection; and iv) the expression of phthiocerol dimycocerosate (PDIM), an Mtb cell envelope lipid. These characteristics of Mtb-HT and Mtb-LT may thus link Mtb-intrinsic factors to differential regulation of the early innate immune response (the Mtb-AM interaction) that leads to the development of distinct adaptive immunity that in turn, governs the kinetics and frequency with which asymptomatic infection progresses to disease. PREDICT29 (segregates progressors vs nonprogressors), in conjunction with the ACS-COR signature (identifies individuals at a later phase of infection), enables the placement of subjects in our cohorts infected with Mtb-HT and Mtb-LT at the early phase of infection that are progressors or nonprogressors or late phase of infection. A combination of ex vivo cellular systems, singe-cell RNA-seq analysis, hi-dimensional mass cytometry, and Nanostring technology will be employed to characterize the immune response exhibited by these various subgroups. We propose to test the following hypothesis: i) Mtb-HT and Mtb-LT elicit differential AM response; ii) Disparate T cell and antibody response in HHC infected with Mtb-HT and Mtb-LT differentially regulate the immunopathology and progression to disease; iii) memory T cells play a role in regulating infection progression. Immunological analysis of these subgroups comprising Mtb-HT and Mtb-LT infected subjects in specific phase of infection, with a focus on the early Mtb-AM interaction, adaptive T cell and antibody response, will provide a large body of information that will shed light on the mechanisms that regulate infection and disease outcomes in the context of progressors and nonprogressors and Mtb- intrinsic factors.