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.

项目摘要 人类结核病（TB）主要由结核分枝杆菌（Mtb）引起， 由于现有药物和疫苗不足，全球健康面临挑战。最 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 用于预防结核病;然而，其功效差异很大。今天，至少有52个国家报告说， 不能治愈或控制的耐多药和广泛耐药结核病例 目前的结核病治疗。因此，迫切需要开发新的疗法/疫苗，其有效地预防或治疗癌症。 治愈肺结核已经确定的是，针对Mtb的适应性免疫应答的产生发生在 次级淋巴器官（SLO）中的生殖中心（GC），如脾脏和病变引流淋巴结， 抗原递呈细胞（APC）与抗原特异性循环T和B淋巴细胞克隆性相互作用 扩散并扩散到感染部位。我们发现接种卡介苗并暴露于 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的， 比单独BCG更长期的保护，如通过减少的Mtb细菌负荷和炎性 感染的进展。有趣的是，这些小鼠的肺部也出现了异位生发中心（eGC 并具有增加的B细胞数量和更高水平的抗Mtb细胞裂解物特异性伊加和IgG抗体。 这些发现表明，NTM和B细胞在产生保护性免疫中起着关键作用， 肺Mtb感染，并且这些小鼠中eGC的形成是这种改善的免疫力的关键因素。 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。 了解结核病发病机制和开发有效疫苗和治疗方法重要问题。在此K99/R 00 应用，我们提出了三个目标：1）调查肺中eGC和常规eGC之间的关键差异 淋巴结中的GC，2）评估NTM和B细胞在eGC刺激中的作用，和3）表征 eGC B细胞对Mtb抗原的抗原特异性和亲和力。这项提案的结果将给我们带来一个 进一步了解B细胞和抗体介导的结核病保护机制。