Immune Determinants of the Course of Mycobacterium tuberculosis infection and Disease

摘要-项目2结核分枝杆菌（Mtb）初次感染与 肺泡巨噬细胞（AM）和活动性疾病的发展是一个连续体，其中无症状 感染可能在延长的时间内进展为结核病（TB）。主持人回应说， 随着感染向疾病的发展，必须演变，这一点尚未确定。同样不清楚的是， 结核病-调节宿主反应的内在因素，因此，结核病进展的动力学 感染疾病。我们已经表征了一种生物标志物特征（PREDICT 29），可以预测 感染进展的风险。临床流行病学研究确定了2类结核分枝杆菌， 指示病例中的杆菌在家庭接触者中传播引起感染的能力 (HHC)Mtb-HT（高透射率）和Mtb-LT（低透射率）。胸部X线显示Mtb-HT IC 空洞性疾病的发生率增加。C3 HeB/FeJ小鼠中Mtb-HT和Mtb-LT的分析显示 两种菌株在i）AM中引起的反应; ii）免疫病理学 模式，肺坏死病变仅在Mtb-HT感染的小鼠中明显; iii）在Mtb-HT感染期间的T细胞应答， 感染的慢性期;以及iv）Mtb细胞--邻苯二甲酸二蜡酯（PDIM）的表达 包膜脂质因此，Mtb-HT和Mtb-LT的这些特征可能将Mtb-内在因素与分化相关。 调节早期先天免疫反应（Mtb-AM相互作用），导致 不同的适应性免疫，反过来，控制动力学和频率， 感染发展为疾病。PREDICT 29（分离进展者与非进展者）， 与ACS-COR签名结合（识别感染后期的个体）， 能够在早期阶段将受试者置于我们感染Mtb-HT和Mtb-LT的队列中 感染的进展者或非进展者或晚期感染。体外结合 细胞系统、单细胞RNA-seq分析、hi-dimensional mass cytometry和Nanostring技术 将用于表征这些不同亚组所表现出的免疫应答。我们提出 为了检验以下假设：i）Mtb-HT和Mtb-LT引起不同的AM应答; ii）不同的T细胞和 Mtb-HT和Mtb-LT感染的HHC中的抗体应答差异性地调节HHC中的免疫应答。 免疫病理学和疾病进展; iii）记忆T细胞在调节感染中起作用 进展包括Mtb-HT和Mtb-LT感染的这些亚组的免疫学分析 受试者在感染的特定阶段，重点是早期Mtb-AM相互作用，适应性T细胞和 抗体反应，将提供大量的信息，将阐明机制， 在进展者和非进展者以及Mtb的背景下调节感染和疾病结果， 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.