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: 10625356
• 负责人: Grant de Vos Theron
• 金额: $ 12.8万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625356
• 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; 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; IL17 gene; Immune; Immune response; Immunity; Immunologic Markers; Immunologics; Immunology; Impairment; Infection; Inflammation; Inflammatory; Interferon Type II; Interleukin-1; Interleukin-4; Interleukin-6; Knowledge; Link; Long-Term Effects; Lower respiratory tract structure; Lung; Lung diseases; Lung immune response; Macrophage; Mass Fragmentography; Matrix Metalloproteinases; Measurement; Measures; Metabolic; Metadata; Methods; Mouth Diseases; Mus; Mycobacterium tuberculosis; New York; Oral; Outcome; Pathogenesis; Patient Recruitments; Patients; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Population; Predisposition; Prevotella; Probiotics; Procedures; Production; Pulmonary Tuberculosis; RNA; Regimen; Relapse; Research; 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; longitudinal analysis; lung microbiota; metabolome; microbial; microbial community; microbial host; microbiome; microbiota; mortality; nano-string; non-tuberculosis mycobacteria; novel; prebiotics; programs; public health emergency; recruit; resilience; respiratory health; respiratory microbiota; scale up; seropositive; therapeutic target; tissue repair; treatment response; 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的发病机制很重要，但是我们对其的了解还不够。 结核病 (TB) 是世界上最重要的肺部疾病，这一备受争议的疾病中，微生物组的作用是 在撒哈拉以南非洲地区，即使采用抗逆转录病毒治疗，艾滋病毒也会加剧结核病。 活动性结核病的发病部位（支气管肺泡腔）是一个独特的疾病。 环境和免疫学生态位，但令人惊讶的是，我们不知道其微生物群的研究不足。 类群，包括对肺部健康重要的类群（口腔厌氧发酵罐），与细菌发酵相关 最终产物，如短链脂肪酸 (SCFA)，可能会影响结核病和组织的免疫控制 此外，结核病治疗方案包含数千剂抗生素，但其对人体的长期影响。 因此，我们迄今为止尚不清楚肺部微生物群的特征，因此缺乏排除的关键基础知识。 研究肺部微生物群作为改善结核病结果的潜在诊断或治疗目标。 我们将检验我们的中心假设，即疾病部位口腔厌氧发酵罐与升高的 肺短链脂肪酸 (SCFA) 以及结核病病例 (n=50) 和治疗时受损的炎症和组织修复生物标志物 最终，这些分类群和生物标志物仍然受到干扰，但一年后会有所改善，我们将招募同等数量的人。 我们位于开普敦的结核病艾滋病毒高负担地点的艾滋病毒阳性患者我们将使用以下方法检验我们的中心假设。 目标 1 将使用改良的支气管肺泡灌洗 (BAL) 程序来比较疾病部位。 目标 2 将在每次治疗前表征对侧未患病肺组织中的微生物群。 治疗前的肺部部位、特定分类群、短链脂肪酸、炎症和组织修复之间的关联 生物标志物，并研究将 SCFA 添加到离体刺激的 BAL 细胞中是否会损害免疫标志物 目标 3 将在治疗结束时通过支气管镜检查对患者重新取样。 一年后，重复测量每个肺部部位的微生物群、SCFA 和宿主生物标志物。 如果疾病部位与微生物群受到干扰有关，通过短链脂肪酸 SCFA 与受损的肺功能相关 免疫和组织修复，包括治疗后，它将证明微生物群和长期结核病临床研究的合理性 结果（例如进展、治疗失败、复发）需要大量且昂贵的试验才能实现。 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改良支气管镜检查和 BAL 微生物群采样的转移 程序（需要最大限度地减少低微生物丰度下呼吸道标本的交叉污染）和 领先的计算专业知识（需要与生物标志物和生物标志物一起共同分析序列数据） 临床数据）从纽约大学到斯泰伦博斯大学（SU）。 将通过研究和培训访问在每个领域进行培训，长期目标是建立一个研究 SU 的肺部微生物群和呼吸系统健康项目。

项目成果

Clinical utility of C-reactive protein-based triage for presumptive pulmonary tuberculosis in South African adults.

• DOI: 10.1016/j.jinf.2022.10.041
• 发表时间: 2023-01
• 期刊: JOURNAL OF INFECTION
• 影响因子: 28.2
• 作者: Calderwood, Claire J.;Reeve, Byron W. P.;Mann, Tiffeney;Palmer, Zaida;Nyawo, Georgina;Mishra, Hridesh;Ndlangalavu, Gcobisa;Abubakar, Ibrahim;Noursadeghi, Mahdad;Theron, Grant;Gupta, Rishi K.
• 通讯作者: Gupta, Rishi K.

Mycobacterium tuberculosis Transmission in High-Incidence Settings-New Paradigms and Insights.

• DOI: 10.3390/pathogens11111228
• 发表时间: 2022-10-25
• 期刊: Pathogens (Basel, Switzerland)

Trauma, posttraumatic stress symptoms, and alcohol-use initiation in children.

儿童的创伤、创伤后应激症状和酗酒。

• DOI: 10.15288/jsad.2010.71.326
• 发表时间: 2010
• 期刊: Journal of studies on alcohol and drugs
• 影响因子: 3.4
• 作者: Wu,Ping;Bird,HectorR;Liu,Xinhua;Duarte,CristianeS;Fuller,Cordelia;Fan,Bin;Shen,Sa;Canino,GlorisaJ
• 通讯作者: Canino,GlorisaJ

More than Mycobacterium tuberculosis: site-of-disease microbial communities, and their functional and clinical profiles in tuberculous lymphadenitis.

• DOI: 10.1136/thorax-2022-219103
• 发表时间: 2023-03
• 期刊: Thorax
• 影响因子: 10
• 作者: Nyawo GR;Naidoo CC;Wu B;Sulaiman I;Clemente JC;Li Y;Minnies S;Reeve BWP;Moodley S;Rautenbach C;Wright C;Singh S;Whitelaw A;Schubert P;Warren R;Segal L;Theron G
• 通讯作者: Theron G

Immunologic and imaging signatures in post tuberculosis lung disease.

• DOI: 10.1016/j.tube.2022.102244
• 发表时间: 2022-09
• 期刊: TUBERCULOSIS
• 影响因子: 3.2
• 作者: Singh, S.;Allwood, B. W.;Chiyaka, T. L.;Kleyhans, L.;Naidoo, C. C.;Moodley, S.;Theron, G.;Segal, L. N.
• 通讯作者: Segal, L. N.