Genetic determinants of inter-individual variation in the dynamic transcriptional innate immune response to Mycobacterium tuberculosis

项目总结 传染病是全世界主要的公共卫生负担。结核病(TB)，由 据估计，全世界每年有近200万人死于结核分枝杆菌(Mtb)。 独自一人。值得注意的是，人类对包括结核分枝杆菌在内的许多病原体的易感性表现出显著的差异。 可以说，这种异质性是由免疫反应的变异引起的，免疫反应负责预防 和控制感染。尽管结核杆菌易感性的个体间差异占相当大的比例 感染可以归因于环境因素，很大一部分是由于宿主遗传因素。这个 宿主遗传因素在临床结核病易感性中的重要性已被双胞胎和家庭证明 学习。然而，导致结核分枝杆菌易感性个体间差异的潜在遗传因素 感染在很大程度上仍是未知的，特别是在人口层面。利用职能部门的综合专业知识 基因组学、计算生物学、人类免疫学和群体遗传学，我建议：(I) 描述一下 结核分枝杆菌感染的先天免疫反应中的个体间和种群间转录差异； MAP表达与结核分枝杆菌感染反应变异相关的数量性状基因座(EQTL)； 以及(Iii)确定最近的正选择在形成与祖先相关的基因差异中的作用 表情。这项工作将对个体间的遗传决定因素产生前所未有的洞察力。 以及对结核分枝杆菌感染的转录先天免疫反应的群体相关变异。此外， 这些努力将建立创新的、新颖的和以经验为基础的转录特征分析战略，以 准确定位极有希望的结核分枝杆菌易感性的候选基因，这将使我们能够识别个体 他们患结核病的风险增加，结核病是现代人面临的最大健康负担之一。

PROJECT SUMMARY Infectious diseases are a major public health burden throughout the world. Tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis (Mtb), is estimated to kill nearly 2 million individuals worldwide every year alone. Notably, humans show remarkable differences in susceptibility to many pathogens, including Mtb. Arguably, this heterogeneity arises from variation in the immune response, which is responsible for preventing and controlling infection. Although a significant proportion of inter-individual variation in susceptibility to Mtb infection can be attributed to environmental factors, a substantial portion is due to host genetic factors. The importance of host genetic factors in susceptibility to clinical TB has been demonstrated by twin and family studies. However, the underlying genetic factors that drive inter-individual differences in susceptibility to Mtb infection remain largely unknown, especially at the population level. Using combined expertise in functional genomics, computational biology, human immunology, and population genetics, I propose to: (i) characterize the inter-individual and inter-population transcriptional variation in the innate immune response to Mtb infection; (ii) map expression quantitative trait loci (eQTLs) that are associated with variation in the response to Mtb infection ; and (iii) determine the role of recent positive selection in shaping ancestry-associated differences in gene expression. This work will yield unprecedented insight into the genetic determinants underlying inter-individual and population-associated variation in the transcriptional innate immune response to Mtb infection. Further, these efforts will establish innovative, novel, and empirically-grounded transcriptional profiling strategies to pinpoint highly-promising genetic candidates for Mtb susceptibility, which will allow us to identify the individuals who are at increased risk for TB, one of the greatest health burdens facing modern human populations.