Pre- and post-treatment lung microbiota, metabolome and immune signatures at the site of disease in patients with active pulmonary tuberculosis

活动性肺结核患者治疗前和治疗后的肺部微生物群、代谢组和疾病部位的免疫特征

• 批准号: 10445329
• 负责人: Grant de Vos Theron
• 金额: $ 13.09万
• 依托单位: STELLENBOSCH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-11 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10445329
• 关键词: Acute-Phase Proteins; Aerosols; Affect; Africa South of the Sahara; African; Aftercare; Anaerobic Bacteria; Antibiotics; Area; Bacteria; Bioinformatics; Biological Markers; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Bronchoscopy; CD4 Positive T Lymphocytes; Cause of Death; Cells; Cessation of life; Chest; Chronic; Clinical; Clinical Data; Clinical Trials; Communicable Diseases; Complex; Computing Methodologies; Contralateral; Custom; Data; Diagnostic; Disease; Dose; Epidemiology; FGF2 gene; Fermentation; Foundations; Growth Factor; HIV; HIV Seronegativity; HIV Seropositivity; HIV/TB; Health; Helicobacter; Hemophilus; Human Microbiome; Human body; Immune; Immune response; Immunity; Immunologic Markers; Immunologics; Immunology; Impairment; Inflammation; Inflammatory; Interferon Type II; Interleukin-1; Interleukin-17; Interleukin-4; Interleukin-6; Knowledge; Link; Long-Term Effects; Lower respiratory tract structure; Lung; Lung diseases; Lung immune response; Mass Fragmentography; Matrix Metalloproteinases; Measurement; Measures; Metabolic; Metadata; Methods; Mouth Diseases; Mus; Mycobacterium tuberculosis; New York; Outcome; Pathogenesis; Patient Recruitments; Patients; Peptide Hydrolases; Persons; Population; Predisposition; Prevotella; Probiotics; Procedures; Production; Pulmonary Tuberculosis; RNA; Regimen; Relapse; Research; Research Training; Respiratory Disease; Ribosomal RNA; Role; Sampling; Scientist; Serum; Site; South Africa; South African; Specimen; Structure of parenchyma of lung; T-Cell Depletion; T-Lymphocyte; T-Lymphocyte Epitopes; TNF gene; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Training; Transforming Growth Factor beta; Treatment Failure; Tuberculosis; United States; Universities; Vaccines; Vascular Endothelial Growth Factors; Veillonella; Visit; Volatile Fatty Acids; antiretroviral therapy; bacterial community; cytokine; gut microbiota; host microbiota; improved; improved outcome; lung microbiota; macrophage; metabolome; microbial; microbial community; microbial host; microbiome; microbiota; mortality; nano-string; non-tuberculosis mycobacteria; novel; oral anaerobes; prebiotics; programs; public health emergency; recruit; resilience; respiratory health; respiratory microbiota; scale up; seropositive; therapeutic target; tissue repair; treatment response; treatment site; tuberculosis treatment

SUMMARY The human microbiome is important for infectious disease pathogenesis. However, our understanding of the microbiome’s role in tuberculosis (TB), which is arguably the most important lung disease in the world, is extremely limited. In sub-Saharan Africa, TB is exacerbated by HIV which, even with antiretroviral therapy, results in reduced pulmonary immunity. The site-of-disease in active TB (bronchoalveolar space) is a unique environmental and immunological niche but its microbiota is surprisingly understudied. We do not know how taxa, including those important for lung heath (oral anaerobic fermenters), correlate with bacterial fermentation end-products like short chain fatty acids (SCFAs), which may influence immunological control of TB and tissue repair. Furthermore, the TB regimen is comprised of thousands of doses of antibiotics yet its long-term effect on the lung microbiota is hitherto uncharacterized. We hence lack key foundational knowledge that precludes research on the lung microbiota as a potential diagnostic or therapeutic target to improve TB outcomes. We will test our central hypothesis that site-of-disease oral anaerobic fermenters are associated with elevated pulmonary SCFAs and impaired inflammation and tissue repair biomarkers in TB cases (n=50) and, at treatment end, these taxa and biomarkers remain perturbed but improve a year later. We will recruit an equal number of HIV-positive patients at our high TB-HIV burden site in Cape Town. We will test our central hypothesis using three aims. Aim 1 will, using a modified bronchoalveolar lavage (BAL) procedure, compare the site-of-disease microbiota to that in contralateral non-diseased lung tissue before treatment. Aim 2 will characterize, at each lung site before treatment, the association between specific taxa, SCFAs, inflammation and tissue repair biomarkers, and investigate whether SCFA addition to ex vivo stimulated BAL cells impairs immune marker release in a dose-dependent manner. Aim 3 will re-sample patients by bronchoscopy at treatment end and a year later, and repeat measurements of the microbiota, SCFAs, and host biomarkers at each lung site. If the site-of-disease is associated with a perturbed microbiota, linked via SCFAs, to impaired pulmonary immunity and tissue repair, including after treatment, it will justify study of the microbiota and long-term TB clinical outcomes (e.g., progression, treatment failure, relapse), which requires large and expensive trials. It will enable research on tests or therapeutic interventions (antibiotics, drugs, prebiotics, vaccines) that target the microbiota. Key to achieving our aims are the transfer of the modified bronchoscopy and BAL microbiota sampling procedure (required to minimize cross contamination in low microbial abundance lower airway specimens) and leading-edge computational expertise (required to co-analyze sequence data in conjunction with biomarker and clinical data) from New York University to Stellenbosch University (SU). South African clinicians and scientists will train in each area by through research and training visits with the long-term aim of establishing a research program on the lung microbiota and respiratory health at SU.

摘要 人体微生物群在传染病发病机制中起着重要作用。然而，我们对 微生物组在结核病中的作用是，结核病可以说是世界上最重要的肺部疾病 非常有限。在撒哈拉以南非洲，艾滋病毒会加剧结核病，即使在抗逆转录病毒治疗的情况下，结果也是如此 导致肺部免疫力下降。活动性肺结核(支气管肺泡腔)的发病部位是独一无二的 环境和免疫学利基，但其微生物区系令人惊讶地研究不足。我们不知道如何 分类群，包括那些对肺部健康很重要的分类群(口腔厌氧发酵菌)，与细菌发酵有关。 可能影响结核病和组织免疫控制的终端产物，如短链脂肪酸(SCFA) 修理。此外，结核病方案是由数千剂抗生素组成的，但它对 到目前为止，肺微生物区系还没有确定特征。因此，我们缺乏关键的基础知识，无法排除 将肺微生物区系作为改善结核病预后的潜在诊断或治疗目标的研究。 我们将验证我们的中心假设，即病位口腔厌氧发酵菌与升高的 肺结核患者(n=50)和治疗时肺内单链脂肪酸与受损的炎症和组织修复生物标记物 结束时，这些分类群和生物标记物仍然受到干扰，但一年后有所改善。我们将招募同等数量的 我们在开普敦的高结核病-艾滋病毒负担地点的艾滋病毒阳性患者。我们将使用以下内容来测试我们的中心假设 三个目标。目标1将使用一种改进的支气管肺泡灌洗(BAL)程序，比较病变部位 治疗前对侧非病变肺组织的微生物区系。目标2将分别描述 治疗前肺组织部位、特异性类群、单链脂肪酸、炎症和组织修复之间的关系 生物标志物，并研究SCFA加入体外刺激的BAL细胞是否损害免疫标志物 以剂量依赖的方式释放。AIM 3将在治疗结束时通过支气管镜对患者进行重新采样 一年后，重复测量每个肺部位的微生物区系、单链脂肪酸和宿主生物标记物。 如果发病部位与扰动的微生物区系有关，微生物区系通过单链脂肪酸与受损的肺 免疫和组织修复，包括治疗后，这将证明微生物区系和长期结核病临床研究的合理性。 结果(如进展、治疗失败、复发)，这需要进行大规模且昂贵的试验。它将使 针对微生物区系的测试或治疗干预(抗生素、药物、益生菌、疫苗)的研究。 实现我们目标的关键是转移改良的支气管镜检查和BAL微生物区系采样 程序(为最大限度地减少低微生物丰度下呼吸道标本的交叉污染所需)和 前沿计算专业知识(需要与BioMarker和 临床数据)从纽约大学到斯泰伦博什大学(苏州)。南非临床医生和科学家 将通过研究和培训访问在每个领域进行培训，长期目标是建立研究 苏州大学关于肺部微生物区系和呼吸健康的计划。