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

项目摘要 传染病是全世界公共卫生的主要负担。结核病（TB），由 结核分枝杆菌（Mycobacterium tuberculosis，Mtb）是一种病原体，据估计每年在全世界范围内杀死近200万人 一个人值得注意的是，人类在对许多病原体（包括Mtb）的易感性方面显示出显著差异。 可以说，这种异质性是由免疫反应的变化引起的，免疫反应负责预防 控制感染。虽然结核病易感性的个体间差异占很大比例， 感染可归因于环境因素，相当大一部分是由于宿主遗传因素。的 宿主遗传因素在临床结核病易感性中重要性已被双胞胎和家庭所证实 问题研究然而，潜在的遗传因素，驱动个体间的差异，易感性结核病 感染情况在很大程度上仍不为人所知，特别是在人口一级。在职能部门利用综合专业知识 基因组学、计算生物学、人类免疫学和群体遗传学，我建议：（i） 表征 对Mtb感染的先天免疫应答中的个体间和群体间转录变异;（ii） 定位与对Mtb感染的应答变化相关的表达数量性状基因座（eQTL）; 和（iii）确定最近的积极选择在形成与祖先相关的基因差异中的作用。 表情这项工作将产生前所未有的深入了解遗传决定因素的基础上，个体间 以及对Mtb感染的转录先天免疫应答中的群体相关变异。此外，本发明还 这些努力将建立创新的、新颖的和基于实验的转录谱分析策略， 确定结核病易感性的高度有希望的遗传候选人，这将使我们能够识别个体 结核病是现代人类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.