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.

总结