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.

概括 人类微生物组对于传染病发病机理很重要。但是，我们对 微生物组在结核病（TB）中的作用，可以说是世界上最重要的肺部疾病，是 极限限制。在撒哈拉以南非洲，HIV加剧了结核病，即使使用抗逆转录病毒疗法，TB也会结果 在降低的肺免疫中。活性结核病（支气管肺泡空间）中的疾病部位是独特的 环境和免疫学生态位，但其菌群令人惊讶地理解。我们不知道如何 分类单元，包括对肺部热（口服厌氧发酵剂）的分类单元，与细菌发酵相关 最终产品如短链脂肪酸（SCFA），可能影响TB和组织的免疫控制 维修。此外，结核病方案由数千剂抗生素组成，但其长期影响 肺微生物群被隐藏了未表征。因此，我们缺乏排除的关键基础知识 研究肺微生物群是改善结核病预后的潜在诊断或治疗靶点。 我们将测试我们的中心假设，即口服厌氧发酵罐与升高有关 结核病病例（n = 50）和治疗时，肺SCFA和注射和组织修复生物标志物受损和组织修复生物标志物 最后，这些分类单元和生物标志物仍然受到干扰，但一年后有所改善。我们将招募相等的数量 我们位于开普敦的TB-HIV Burnen站点的HIV阳性患者。我们将使用 三个目标。 AIM 1将使用改良的支气管肺泡灌洗（BAL）程序进行比较饮食地点 在治疗前对比对比未切除的肺组织的微生物群。 AIM 2会在每个 治疗前肺部，特定分类单元，SCFA，注射和组织修复之间的关联 生物标志物，并研究SCFA是否添加为离体刺激BAL细胞会损害免疫标记物 以剂量依赖的方式释放。 AIM 3将通过支气管镜检查在治疗端重新样本和A 一年后，并在每个肺部重复测量微生物群，SCFA和宿主生物标志物。 如果疾病部位与通过SCFA相关的扰动微生物群有关，以损害肺部 免疫和组织修复，包括治疗后，它将证明对菌群和长期结核病临床的研究是合理的 结果（例如进展，治疗失败，退休），需要大量昂贵的试验。它将启用 针对微生物群的测试或治疗干预措施（抗生素，药物，益生元，疫苗）的研究。 实现我们目标的关键是修饰的支气管镜检查和BAL Microbiota采样的转移 程序（需要在低微生物丰度低呼吸道标本中最大程度地减少交叉污染）和 领先的计算专业知识（需要与生物标志物共同分析序列数据和 临床数据）从纽约大学到斯泰伦博斯大学（SU）。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训练，以建立研究的长期目的 SU的肺微生物群和呼吸健康的计划。