Investigation of responses to Mycobacterium tuberculosis complex lineages by different African host population: Implications for host-directed therapies

不同非洲宿主人群对结核分枝杆菌复杂谱系反应的调查：对宿主导向疗法的影响

• 批准号: 10153912
• 负责人: Leopold Tientcheu Djomkam
• 金额: $ 11.15万
• 依托单位: MEDICAL RESEARCH COUNCIL UNIT THE GAMBIA AT THE LONDON SCHOOL OF HYGIENE & TROPICAL MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-22 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153912
• 关键词: Accounting; Address; Affect; Africa; African; Aftercare; Antibiotics; Award; Bacteria; Bioinformatics; Biological Assay; Biological Markers; Blood; Case Study; Cells; Clinical; Clinical Trials; Clinical Trials Design; Colony-forming units; Communicable Diseases; Competence; Complex; Control Groups; Country; Data Analyses; Development; Disease; Disease Outcome; Doctor of Philosophy; Drug resistance; Drug resistance in tuberculosis; Educational workshop; Epidemiology; Ethnic Origin; Ethnic group; FCGR3B gene; Failure; Flow Cytometry; Fluorescence; Funding; Future; Gambia; Gelatinase B; Gene Expression; Genes; Genetic; Genetic Variation; Genomics; Gleevec; Goals; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Heterogeneity; Hour; Human; Human Genetics; Imatinib; Immune; Immune response; Immunologics; Immunotherapeutic agent; In Vitro; Incubated; Individual; Infection; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-10; Interleukin-12; Interleukin-15; Interleukin-6; Interstitial Collagenase; Investigation; Leadership; Liquid substance; Lysosomes; Measurement; Measures; Medical; Mentors; Mentorship; Metabolism; Modeling; Mononuclear; Mycobacterium africanum; Mycobacterium tuberculosis; Myelogenous; Outcome; Participant; Pathway interactions; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Phenotype; Population; Population Heterogeneity; Positioning Attribute; Production; Proto-Oncogene Proteins c-abl; Protocols documentation; Pulmonary Tuberculosis; Quantitative Reverse Transcriptase PCR; RNA; RNA analysis; Regimen; Reporter Genes; Research; Research Personnel; Resistance; Resolution; Risk; Signal Pathway; Site; Societies; South Africa; South African; Sputum; TNF gene; Testing; Therapeutic; Therapeutic Clinical Trial; Therapeutic Trials; Time; Tissue-Specific Gene Expression; Training; Treatment outcome; Tuberculosis; Universities; Ursidae Family; Venous; Work; Writing; anakinra; arm; base; career; chemokine; compliance behavior; cytokine; design; differential expression; economic impact; experience; genetic signature; immunoregulation; improved; insight; low and middle-income countries; luminescence; macrophage; monocyte; multidisciplinary; novel; predicting response; pressure; response; skills; success; therapeutic candidate; therapeutic development; therapeutic target; tool; transcriptome sequencing; transcriptomics; tuberculosis treatment; young adult

Tuberculosis (TB) has evolved with human populations such that the clades of Mycobacterium tuberculosis complex (MTBC) are closely associated with human migratory pathways out of the rift valley. TB and the human response to bacteria are thus closely aligned but may have differed under evironmental specific selective pressures. Such differences have important implications for the treatement of TB, not only for the use of antibiotics, where ethnicity is a contributor to antibiotic metabolism, but also with the development of novel immunotherapeutics, otherswise called host-directed therapeutics (HDTs). Here we propose to determine whether ethnicity, particularly amongst West African and South African poulations contributes to host immune responses to endemic MTBC lineages. Moreover, we will correlate response to these lineages with efficacy of HDTs. In this study we will use as a test case Gleevec (Imatinib), which targets the Abl tyrosine kinases, stimulates lysosomes production and augments myeloid response to TB. Imatinib is currenlty being tested in Atlanta and South Africa againist active pulmonary TB. My goal for this 5-years K43 award is to gain critical skills in transcriptomics bioinformatics and experience in HDT clinical trials to develop both my independence and a project suitable for future funding to assess the capacity of HDTs to act broadly across MTBC clades and population of different ethnicity. Such studies will be vital to establishing the general efficacy of new HDTs across human populations, and to determining the types of immune responses that are broadly efficacious and durable. MTBC genetic diversity mirrors Africa's great human genetic and environmental diversity. For instance, in West Africa, M. africanum (Maf)-lineage-6 causes about 40% and M. tuberculosis (Mtb)-lineage-4 60% of all TB. Conversely, in South Africa 65% of TB is caused by Mtb-lineage-4 and about 35% is attributed to Mtb-lineage-2, recently imported to the region. These heterogeneities affect MTBC infection and treatment outcomes, and should be particularly considered in novel HDT approaches. I will address this from three complementary angles. First, by determining the differential gene expression pathways elicited by sympatric versus allopatric MTBC lineages. Secondly, harness the top express genes to predict the responses to novel HDTs molecules. Thirdly, investigate in-vitro how Gambian and South African monocytes inhibit the growth of allopatric compared to sympatric MTBC lineages in the absence or presence of candidate HDTs molecules and measure the cellular and inflammatory response differences. The K43 will equip me with further skills in Transcriptomics, Bioinformatics, integrated data analysis approaches as well as research leadership to rationally design HDTs trials for different African populations and effectively collaborate with infectious disease medical experts throughout my career. My mentorship team comprises established researchers in TB clinical trials and genomic analysis experts (The Gambia and South Africa mentors) and TB HDT development (US mentor). I will leverage my time between the field research in The Gambia and South Africa and will take advantage of multiple grant-writing workshops available at Emory University to be in an excellent position to submit an R01 application in the fifth year to continue developing HDTs for infectious disease in Africa.

结核病（TB）随着人类的发展而发展， 复杂的（MTBC）与人类迁移出裂谷的路径密切相关。TB和 因此，人类对细菌反应是紧密一致的，但在环境特异性下可能有所不同。 选择性压力这种差异对结核病的控制有重要意义，不仅是因为使用 抗生素，其中种族是抗生素代谢的贡献者，但也随着新的抗生素的发展， 免疫疗法，也称为宿主导向疗法（HDTs）。在这里，我们建议确定 种族，特别是西非和南非的种族是否有助于宿主免疫 对地方性MTBC谱系的反应。此外，我们将把对这些谱系的反应与 HDTs。在这项研究中，我们将使用靶向Abl酪氨酸激酶的Gleevec（伊马替尼）作为测试案例， 刺激溶酶体产生并增强对TB的骨髓反应。伊马替尼目前正在测试中， 亚特兰大和南非的肺结核患者。我的目标是这个5年K43奖是获得关键 在转录组学生物信息学和HDT临床试验的经验，以发展我的独立性， 以及一个适合于未来资助的项目，以评估HDT在MTBC分支中广泛发挥作用的能力 不同种族的人口。这些研究对于确定新型HDTs的总体疗效至关重要 并确定广泛有效的免疫应答类型， 耐用. MTBC遗传多样性反映了非洲巨大的人类遗传和环境多样性。为 例如，在西非，M. africanum（Maf）-lineage-6引起的感染率约为40%;结核病（Mtb）-谱系-4 60%的结核病。相反，在南非，65%的结核病是由Mtb-谱系-4引起的，约35%是归因于 结核分枝杆菌谱系2，最近进口到该地区。这些异质性影响MTBC感染和治疗 结果，并应特别考虑在新的HDT方法。我会从三点开始 互补角首先，通过确定由同域表达引起的差异基因表达途径， 与异地MTBC谱系相比。第二，利用高表达基因来预测对新药物的反应， HDTs分子。第三，研究冈比亚和南非的单核细胞如何在体外抑制人单核细胞的生长。 在不存在或存在候选HDTs分子的情况下，与同域MTBC谱系相比， 并测量细胞和炎症反应的差异。K43将为我提供更多的技能， 转录组学、生物信息学、综合数据分析方法以及研究领导力， 为不同的非洲人群合理设计HDTs试验，并有效地与传染病合作 医学专家在我的职业生涯中我的导师团队由结核病临床领域的知名研究人员组成 试验和基因组分析专家（冈比亚和南非导师）和TB HDT开发（美国 导师）。我将利用我在冈比亚和南非实地研究之间的时间， 埃默里大学提供的多个赠款写作研讨会的优势是处于一个很好的位置， 在第五年提交R 01申请，继续开发非洲传染病HDT。