Mce transport systems of Mycobacterium tuberculosis

描述（由申请人提供）：结核分枝杆菌是人类结核病的病原体，感染了世界上大约三分之一的人口，每年造成近200万人死亡。治疗现有疾病的新策略和预防新感染的改进疫苗接种方法将需要更好地了解这种病原体在宿主中持续存在并导致疾病的机制。与许多其他细菌病原体不同，M.结核病主要通过分泌多种复杂的小分子与宿主相互作用。使用一种新的遗传学方法，我们已经确定了次级代谢物的生物合成途径和大型多亚基运输系统，共同发挥作用，以促进体内细菌生长和疾病进展。使用M.结核病突变体缺乏生物合成基因的运输系统，我们将确定介导细菌和宿主之间相互作用的新化合物（目的1）。通过表征这些突变体和宿主巨噬细胞之间改变的相互作用，我们将确定这些系统在感染过程中发挥的特定作用（目的2），最后，我们将剖析单个转运蛋白组分的结构和功能，以确定毒力特异性适应，解释这种感染的一些独特生物学（目的3）。

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis, the causative agent of human tuberculosis infects approximately one-third of the world's population and kills nearly two million people each year. New strategies of the treatment of existing disease and improved vaccination methods to prevent new infections will require a greater understanding of the mechanisms used by this pathogen to persist in the host and cause disease. Unlike many other bacterial pathogens, M. tuberculosis interacts with the host largely through the secretion of a wide variety of complex small molecules. Using a new genetic methodology, we have identified secondary metabolite biosynthetic pathways and large multisubunit transport systems that function in concert to promote bacterial growth in vivo and disease progression. Using a panel of M. tuberculosis mutants that lack either transport systems of biosynthetic genes, we will identify the novel compounds that mediate interactions between the bacterium and host (Aim 1). By characterizing the altered interaction between these mutants and the host macrophage, we will determine the the specific roles played by these systems during infection (Aim 2), Finally, we will dissect the structure and functions of individual transporter components to identify virulence-specific adaptations that explain some of the unique biology of this infection (Aim 3).