结核分枝杆菌优势亚型的高致病性进化机制研究

结核分枝杆菌伴随人类已有7万年历史，在与人类的长期共进化过程中分化为多个亚型。我们的前期工作发现在我国广泛流行的优势亚型菌株所具有的高致病性是成功适应人口密度增长这一自然环境改变的结果；同时鉴定出优势亚型为适应宿主体内复杂环境所积累的特有遗传突变，但仅从基因组序列改变很难阐明其机制。由遗传突变导致的不同层次的基因调控网络变化是细菌调控自身以适应环境的重要机制之一。因此我们提出“基因调控网络的改变或重塑是结核菌优势亚型高致病性的遗传基础”的科学假设。本研究拟利用基因组学、转录组学、蛋白组学和、生物信息学等方法探讨优势亚型特有遗传突变及其导致的基因调控网络改变与高致病性的关系，阐明其在进化过程中产生高致病性的生物学机制。本研究成果将丰富和完善微进化过程中多基因相互作用机制的理论；揭示结核菌进化中的关键遗传变异所调控的网络功能，为新药和疫苗的研发提供理论指导。

Tuberculosis is an ancient infectious disease and caused by Mycobacterium tuberculosis (MTB), interacting with human beings for more than 70,000 years. MTB has evolved into various lineages during its long term coevolution with host. In our previous research, the predominant MTB sublineage in China with high prevalence and pathogenicity was identified, as a result of successful adaptation to the increase of human population density in Neolithic Age. Through comparative genomics analysis, we determined the genetic alterations unique to the predominant sublineage. However, it is still elusive how the genomic alterations contribute to the adaptive microevolution of MTB. The remodeling of gene regulatory network is a common mechanism by which bacterial pathogens adapt to different environments. Since the genetic specific mutations of predominant sublineage are mainly enriched in regulatory network, we hypothesize that the remodeling of gene regulatory network is the genetic basis for the increased pathogenicity of the predominant sublineage. In this project, through the approaches of genomics, transcriptomics, proteomics and, bioinformatics, we aim to investigate the mechanisms of gene regulatory network remodeling and how it contributes to the high pathogenicity. The prospective findings of this project will improve our understanding on how multiple genes interact together during the microevolution, and elucidate the key functions by which the genetic alterations play in the regulatory network. Meanwhile, the findings will also provide theoretical guidance for developing new anti-tuberculosis drugs and vaccines.