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 - 项目 2 在初次接触结核分枝杆菌 (Mtb) 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 感染可能会在较长时间内发展为结核病 (TB)。楼主回复说 是否必须随着感染进展为疾病而演变尚未确定。同样不清楚的是 Mtb 调节宿主反应的内在因素，从而调节 Mtb 进展的动力学 感染而发病。我们已经表征了可以预测的生物标志物签名（PREDICT29） 感染进展的风险。临床流行病学研究确定了 2 类 Mtb 指示病例中的杆菌传播导致家庭接触者感染的能力 (HHC)：Mtb-HT（高透射率）和Mtb-LT（低透射率）。显示 Mtb-HT IC 胸部 X 光检查 空洞疾病的发生率增加。 C3HeB/FeJ 小鼠中的 Mtb-HT 和 Mtb-LT 分析揭示 2 个菌株之间的显着差异在于 i) AM 中引发的反应； ii) 免疫病理学 模式，肺部坏死病变仅在 Mtb-HT 感染小鼠中明显； iii) T细胞反应 感染的慢性阶段； iv) phthiocerol dimycocerosate (PDIM)（一种 Mtb 细胞）的表达 包膜脂质。因此，Mtb-HT 和 Mtb-LT 的这些特征可能将 Mtb 内在因素与差异联系起来。 早期先天免疫反应（Mtb-AM 相互作用）的调节，导致发展 独特的适应性免疫反过来又控制着无症状感染的动力学和频率 感染进展为疾病。 PREDICT29（将进展者与非进展者分开），在 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安置在感染 Mtb-HT 和 Mtb-LT 的队列中 进展者或非进展者或感染晚期的感染。离体组合 细胞系统、单细胞 RNA-seq 分析、高维质谱流式分析和 Nanostring 技术 将用于表征这些不同亚组所表现出的免疫反应。我们建议 检验以下假设： i) Mtb-HT 和 Mtb-LT 引起不同的 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细胞在调节感染中发挥作用 进展。对包含 Mtb-HT 和 Mtb-LT 感染的这些亚组进行免疫学分析 感染特定阶段的受试者，重点关注早期 Mtb-AM 相互作用、适应性 T 细胞和 抗体反应，将提供大量信息，阐明抗体反应的机制 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果 内在因素。