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

结核病(TB)随着人类的发展而进化，以至于结核分枝杆菌的分支 复合体(MTBC)与人类走出裂谷的迁移路径密切相关。结核病和 因此，人类对细菌的反应是紧密一致的，但在特定环境下可能会有所不同 有选择性的压力。这些差异对结核病的治疗有着重要的影响，而不仅仅是使用 在抗生素中，种族是抗生素新陈代谢的贡献者，但也伴随着新技术的发展 免疫疗法，又称宿主导向疗法(HDTS)。在这里，我们建议确定 种族，特别是在西非和南非禽类中是否有助于宿主免疫 对地方性MTBC血统的反应。此外，我们将把对这些血统的反应与 HDTS。在这项研究中，我们将使用针对Abl酪氨酸激酶的格列卫(Imatinib)作为测试案例， 刺激溶酶体的产生，增强对结核病的髓系反应。伊马替尼目前正在进行临床试验 亚特兰大和南非被列为活动性肺结核。我这个为期5年的K43奖项的目标是获得关键的 转录学、生物信息学的技能和HDT临床试验的经验培养了我的独立性 以及一个适用于未来资金的项目，以评估HDTS在MTBC分支中广泛行动的能力 和不同种族的人口。这些研究将对确定新的HDTS的总体疗效至关重要 在人类群体中，并确定广泛有效和 经久耐用。母婴传播的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，非洲分枝杆菌(Maf)-谱系-6约占40%，结核分枝杆菌(Mtb)-谱系-4 占所有结核病的60%。相反，在南非，65%的结核病是由Mtb-Lineage-4引起的，大约35%是由Mtb-Lineage-4引起的 到Mtb-Lineage-2，最近进口到该地区。这些异质性影响MTBC的感染和治疗 结果，在新的人类发展疗法方法中应特别加以考虑。我将从三个方面来解决这个问题 互补的角度。首先，通过确定共点引起的差异基因表达途径 与异位MTBC血统的对比。其次，利用最高表达基因来预测对小说的反应 HDTS分子。第三，研究冈比亚和南非单核细胞在体外如何抑制肿瘤细胞的生长。 在没有或存在候选HDTS分子的情况下，异位与同域MTBC谱系的比较 并测量细胞和炎症反应的差异。K43将使我在以下方面拥有更多技能 转录学、生物信息学、综合数据分析方法以及研究领导力 合理设计针对不同非洲人群的HDTS试验，有效协作应对传染病 在我的职业生涯中一直是医学专家。我的导师团队由结核病临床方面的资深研究人员组成 试验和基因组分析专家(冈比亚和南非导师)和结核病HDT开发(美国 导师)。我将利用我在冈比亚和南非进行实地研究的时间，并将 埃默里大学提供多个赠款撰写研讨会的优势，使其处于有利地位 在第五年提交R01申请，继续开发用于非洲传染病的HDTS。

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.