Immune Determinants of the Course of Mycobacterium tuberculosis infection and Disease

结核分枝杆菌感染和疾病过程的免疫决定因素

• 批准号: 10271649
• 负责人: Padmini Salgame
• 金额: $ 50.77万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10271649
• 关键词: Alveolar Macrophages; Antibody Response; Automobile Driving; Bacillus; Blood; Brazil; C3HeB/FeJ Mouse; Cells; Characteristics; Chronic Phase; Clinical; Complex; Cytometry; Data; Development; Diagnosis; Diffuse; Dimensions; Disease; Disease Outcome; Disease Progression; Drug Tolerance; Epidemiology; Evolution; Exhibits; Exposure to; Frequencies; Funding; Gene Expression Profile; Granuloma; Heterogeneity; Household; Human; Immune; Immune response; Immunologics; Immunology; Individual; Infection; Inflammatory; Innate Immune Response; Interleukin-17; Intrinsic factor; Kinetics; Lesion; Light; Link; Lipids; Lung; Machine Learning; Memory; Mus; Mycobacterium tuberculosis; Necrotic Lesion; Pathogenesis; Pathologic; Pattern; Performance; Phase; Play; Population; Process; Prospective cohort study; Pulmonary Pathology; Regulation; Risk; Role; Sampling; Severity of illness; Shapes; Side; Subgroup; System; Systems Biology; T cell response; T memory cell; T-Lymphocyte; Technology; Testing; Therapeutic Intervention; Thoracic Radiography; Time; Translating; Tuberculin Test; Tuberculosis; Uganda; Validation; Work; adaptive immunity; base; biomarker signature; cell envelope; cohort; design; disease transmission; effective intervention; epidemiology study; follow-up; immunopathology; improved; in vivo; indexing; latent infection; liquid chromatography mass spectrometry; nano-string; novel; pathogen; predictive signature; relapse risk; response; transcriptome sequencing; transmission process

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.

摘要 - 与结核分枝杆菌（MTB）初次相遇的项目2 肺泡巨噬细胞（AM）和活动疾病的发展是无症状的连续体 在延长的时间范围内，感染可能发展为结核病（TB）疾病。主机回应 必须随着感染的发展而发展，尚未定义。同样不清楚的角色 MTB内部因素调节宿主反应，因此， 感染疾病。我们已经表征了一个生物标志物签名（Predict29），可以预测 感染进展的风险。临床流行病学研究确定了2类基于MTB 从指数病例的细菌的能力传播以引起家庭接触的感染 （HHC）：MTB-HT（高传输）和MTB-LT（低传输）。显示MTB-HT IC的胸部X射线显示 自杀疾病的频率增加。 C3HEB/FEJ小鼠中MTB-HT和MTB-LT的分析显示 i）AM引起的响应的两种菌株之间的显着差异； ii）免疫病理学 模式，肺坏死病变仅在MTB-HT感染小鼠中明显。 iii）T细胞响应期间 感染的慢性阶段；和iv）苯二酚二氯苯甲酸（PDIM），mtb细胞的表达 信封脂质。 MTB-HT和MTB-LT的这些特征可能因此可以将MTB内在因子与差异联系起来 调节早期先天免疫反应（MTB-AM相互作用），导致发展 从反过来控制无症状的动力学和频率的独特自适应免疫力 感染发展为疾病。预测29（分隔了进度者与非推测器）， 与ACS-COR签名的结合（在感染的后期识别个体）， 使受试者在早期被MTB-HT和MTB-LT感染的同类中放置 感染者是进度者或非培训器或感染后期。离体的组合 蜂窝系统，单核RNA-seq分析，高维质量细胞仪和纳米串技术 将采用这些各种亚组表现出的免疫反应来表征。我们建议 检验以下假设：i）MTB-HT和MTB-LT引起差异AM响应； ii）不同的T细胞和 感染MTB-HT和MTB-LT的HHC中的抗体反应差异调节 免疫病理学和疾病进展； iii）记忆T细胞在调节感染中起作用 进展。这些亚组的免疫学分析包括MTB-HT和MTB-LT感染 特定感染阶段的受试者，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信息，以阐明 在进步者和非培训者和MTB-的背景下，调节感染和疾病结局 内在因素。