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The human lung and lung-draining lymph node response to Mycobacterium tuberculosis

人肺和肺引流淋巴结对结核分枝杆菌的反应

基本信息

批准号：
10666017
负责人：
Roshni Roy Chowdhury
金额：
$ 23.73万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-12 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10666017
关键词：
Acid Fast Bacillae Staining Method Adult Animal Model Antigens Architecture BCG Live Bacillus Biological Response Modifiers CD8-Positive T-Lymphocytes Catalogs Cause of Death Cells Cellular Immunity Clinical Computational algorithm DNA Data Development Effector Cell Epitopes Focal Infection Genetic Transcription Goals Granuloma Granulomatous HIV HIV Seronegativity Hilar Histologic Human Immune Immune response Immunity Immunization Individual Infection Inflammatory Knowledge Lesion Licensing Lung Lung diseases Lung infections Lymph Node Mapping Lymph Node Tuberculosis Lymphatic System Maps Mediastinal Methods Modification Molecular Mus Mycobacterium bovis Mycobacterium tuberculosis Mycobacterium tuberculosis antigens Myeloid Cells Necrosis Organ Organoids Outcome Pathogenesis Patients Phenotype Population Pulmonary Tuberculosis Reaction Research Site Specimen Staging Stains Sterilization Structure Swelling T cell receptor repertoire sequencing T cell response T-Lymphocyte T-Lymphocyte Subsets T-cell receptor repertoire Testing Thoracic Lymph Node Tissues Tuberculosis Tuberculosis Vaccines Vaccination Vaccine Design Vaccines Variant adaptive immune response candidate identification cell mediated immune response comparative complementarity-determining region 3 design draining lymph node effector T cell inflammatory milieu innovation insight interest lung lesion lymph nodes machine learning algorithm mimetics mycobacterial nonhuman primate novel vaccines outcome disparities pathogen public database pulmonary granuloma response stem trafficking transcriptomics transmission process tuberculosis granuloma

项目摘要

Project summary/Abstract This project is focused on gaining conceptual and mechanistic insights into immune mediators that contribute to the development of protective immunity against Mycobacterium tuberculosis (Mtb) in human lung and lung- draining lymph nodes. Although tuberculosis (TB) typically manifests as a pulmonary disease, thoracic lymph nodes are the most common sites of extrapulmonary Mtb infection. Mtb can be reactivated in lymph nodes, leading to the formation of granulomas and Mtb dissemination to the lungs and other organs. Yet, the lymph node response to Mtb in humans remains understudied. A key feature of Mtb pathogenesis is granuloma formation; finely tuned immune responses within these structures determine localized infection outcomes. Here, we aim to perform a comparative assessment of the immune (specifically, T cell) responses within human pulmonary and lymph node granulomas that are successful and unsuccessful in eliminating Mtb. To accomplish this, we propose to characterize specimens with histological evidence of a granulomatous reaction that (a) show negative Acid-Fast-Bacilli (AFB) stain but test positive for the presence of TB-DNA by PCR (reflective of sterilizing immunity or a successful immune response at the granuloma level), and (b) show positive AFB stain (representing an unsuccessful host effort). Studies in animal models have shown that T cells are important in controlling the clinical course of TB and that the T cell response to Mtb antigens is initiated in thoracic lymph nodes and not the lungs. Thus, first, we will test the hypothesis that differences between sterilizing immunity and unsuccessful responses stem from differences in specific effector T cell phenotypes and functions, and their spatial organization in the granulomas. Indeed, our preliminary data show that specific CD8+ T cell responses associate with Mtb clearance at the granuloma level. Our next goal is to use this knowledge to guide the selection of appropriate antigens to re-elicit this response through vaccination. To accomplish this, we will establish tissue- mimetic organoids from lymph nodes, which are the staging grounds for cellular immunity following immunization. We will test the hypothesis that these protective T cell responses that are naturally elicited in granulomas can be induced in lymph node organoids from TB-naïve donors by specific Mtb (not BCG) antigens. Finally, we will employ a combination of T cell receptor sequencing and machine-learning algorithms to identify the precise protective epitopes. Collectively, we expect our results to generate important new insight into the determinants of immune defense in TB, identify candidates for new TB vaccines, and create opportunities for the management of the global burden of tuberculosis.

项目总结/文摘