Non-tuberculous mycobacterium and B cells in the stimulation of ectopic germinal centers and immunological control of pulmonary tuberculosis

非结核分枝杆菌和 B 细胞在异位生发中心刺激和肺结核免疫控制中的作用

• 批准号: 10569865
• 负责人: Taru S. Dutt
• 金额: $ 11.24万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569865
• 关键词: Adoptive Transfer; Affect; Affinity; Animals; Antibiotic Therapy; Antibiotics; Antibodies; Antibody Affinity; Antigen-Presenting Cells; Antigens; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocytes; BCG Live; Bacille Calmette-Guerin vaccination; Binding; Biogenesis; Cells; Clinical; Clonal Expansion; Collaborations; Country; Data; Developing Countries; Development; Disease; Environment; Exposure to; Extreme drug resistant tuberculosis; Foundations; Generations; Genetic; Genus Mycobacterium; Grant; Helper-Inducer T-Lymphocyte; Human; Humoral Immunities; Immune response; Immunity; Immunoglobulin A; Immunoglobulin G; Immunologics; Immunology; Infection; Inflammatory; Knockout Mice; Knowledge; Lesion; Licensing; Lung; Mediating; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium avium; Mycobacterium leprae; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Organ; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phase; Play; Population; Postdoctoral Fellow; Proteome; Public Health; Pulmonary Tuberculosis; Reporting; Research; Role; Signal Pathway; Signal Transduction; Site; Specificity; Spleen; Stimulus; Stromal Cells; Structure of germinal center of lymph node; Tissues; Training; Tuberculosis; Tumor Necrosis Factor-Beta; United States Environmental Protection Agency; Vaccinated; Vaccines; adaptive immune response; career; co-infection; compliance behavior; draining lymph node; drinking water; drug-sensitive; experience; extensive drug resistance; fighting; global health; improved; insight; lymph nodes; non-tuberculosis mycobacteria; novel therapeutics; opportunistic pathogen; prevent; programs; receptor; recruit; response; secondary lymphoid organ; single-cell RNA sequencing; transcriptomics; tuberculosis drugs; tuberculosis immunity; tuberculosis treatment

Project Summary Human tuberculosis (TB) is caused mainly by Mycobacterium tuberculosis (Mtb) and represents an enormous challenge to global health because of the inadequacy of currently available drugs and vaccines. The most common clinical manifestation is pulmonary TB, and Bacille Calmette Guerin (BCG) is the only licensed vaccine for protection against TB; however, its efficacy is highly variable. Today at least 52 countries have reported multidrug-resistant (MDR) and extensive drug-resistant (XDR) TB cases which cannot be cured or contained by current TB therapy. Thus, there is an urgent need to develop new therapies/vaccines that effectively prevent or cure TB. It is well established that the generation of an adaptive immune response against Mtb occurs inside germinal centers (GCs) in secondary lymphoid organs (SLOs), such as spleen and lesion draining lymph nodes, where antigen‐presenting cells (APCs) and antigen-specific circulating T and B lymphocytes interact, clonally expand, and are disseminated to sites of infection. We found that mice vaccinated with BCG and exposed to Mycobacterium avium [a non-tuberculous mycobacterium (NTM)] via drinking water provide more robust and longer-term protection than BCG alone as determined by reduced Mtb bacterial burden and inflammatory progression of infection. Interestingly, these mice also developed ectopic germinal centers (eGC) in the lungs and have an increased number of B-cells and higher levels of anti-Mtb cell lysate-specific IgA and IgG antibodies. These findings suggest that NTM and B-cells play a critical role in generating protective immunity against pulmonary Mtb infection, and the formation of eGC in these mice is a crucial factor in this improved immunity. Thus, investigating the mechanism of eGC formation and the role of NTM and B-cells in its stimulation is an important question to understand TB pathogenesis and develop effective vaccines and therapies. In this K99/R00 application, we propose three aims: 1) investigating the key differences between eGC in lungs and conventional GCs in lymph nodes, 2) evaluating the role of NTM and B-cells in eGC stimulation, and 3) characterizing the antigen-specificity and affinity of eGC B-cells against Mtb antigens. The results of this proposal will bring us one step closer to understanding the B-cell and antibody-mediated mechanisms of protection from TB.

项目概要 人类结核病 (TB) 主要由结核分枝杆菌 (Mtb) 引起，代表着巨大的结核病风险。 由于目前可用的药物和疫苗不足，对全球健康构成了挑战。 常见的临床表现是肺结核，卡介苗（BCG）是唯一获得许可的疫苗 然而，目前至少有 52 个国家报告了其疗效。 无法治愈或遏制的耐多药（MDR）和广泛耐药（XDR）结核病例 因此，迫切需要开发有效预防或治疗的新疗法/疫苗。 众所周知，针对 Mtb 的适应性免疫反应发生在体内。 二级淋巴器官 (SLO) 中的生发中心 (GC)，例如脾脏和病变引流淋巴结， 抗原呈递细胞 (APC) 与抗原特异性循环 T 淋巴细胞和 B 淋巴细胞以克隆方式相互作用 我们发现接种卡介苗并暴露于的小鼠会扩大并传播到感染部位。 鸟分枝杆菌 [一种非结核分枝杆菌 (NTM)] 通过饮用水提供更强大和 通过减少 Mtb 细菌负荷和炎症来确定比单独使用 BCG 具有更长期的保护作用 暗示着，这些小鼠的肺部也出现了异位生发中心（eGC）。 并且 B 细胞数量增加，抗 Mtb 细胞裂解物特异性 IgA 和 IgG 抗体水平更高。 这些发现表明 NTM 和 B 细胞在产生针对病毒的保护性免疫力方面发挥着关键作用。 肺部 Mtb 感染以及这些小鼠中 eGC 的形成是提高免疫力的关键因素。 因此，研究 eGC 形成的机制以及 NTM 和 B 细胞在其刺激中的作用是一个重要的研究方向。 在本 K99/R00 中，这是了解结核病发病机制和开发有效疫苗和疗法的重要问题。 应用中，我们提出了三个目标：1）研究肺部 eGC 与传统的 eGC 之间的主要区别 淋巴结中的 GC，2) 评估 NTM 和 B 细胞在 eGC 刺激中的作用，以及 3) 表征 eGC B 细胞对 Mtb 抗原的抗原特异性和亲和力 这一提案的结果将为我们带来一个结果。 进一步了解 B 细胞和抗体介导的结核病保护机制。