Phage mimicry of mycobacterial signaling

描述（由申请人提供）：结核分枝杆菌比任何其他单一传染性病原体造成更多的人类死亡，并在全球范围内造成相当大的社会和经济损失。众所周知，成人肺结核很难控制，需要使用多种抗生素进行长期治疗。缺乏对这些方案的依从性已经鼓励了多重耐药M菌株的出现。结核 有效控制结核病需要更好的诊断方法、更有效的疫苗和更好的抗分枝杆菌药物，特别是用于治疗潜伏和多重耐药感染。分枝杆菌遗传学的最新进展和几个完整的分枝杆菌基因组序列的可用性带来了相当大的希望的想法，阐明分枝杆菌的生理学，代谢，遗传学和结构的基本原则将导致新的战略控制分枝杆菌感染。目前，我们对这些核心问题的基本方面的分子基础知之甚少，例如为什么这些细菌生长如此缓慢，它们独特的细胞壁是如何合成的，以及分枝杆菌细胞如何交流。阐明这些中心问题对于理解分枝杆菌发病机制的分子基础以及我们如何干预它是很重要的。 噬菌体是了解细菌宿主的有力工具，对于分枝杆菌噬菌体来说也是如此。分枝杆菌噬菌体是与宿主关系极其密切的伙伴;它们不仅依赖宿主的代谢机制进行复制和组装，而且还必须通过复杂而敌对的分枝杆菌细胞壁进入，并在细胞对它们不再有任何用处时找到退出细胞的方法。此外，分枝杆菌噬菌体可能根本不会杀死它们的宿主，而是将它们的DNA整合到宿主染色体中并和平共存。 这个项目的重点是研究分枝杆菌噬菌体模拟分枝杆菌细胞信号通路的方法。我们已经发现分枝杆菌噬菌体Bxbl整合到groEL 1基因中，groEL 1基因是分枝杆菌中的两个groEL基因之一。groEL 1基因的中断导致生物膜成熟的丧失，这显然是由于无法组装用于霉菌酸合成的FAS-II酶复合物。我们建议阐明GroEL 1在生物膜形成和分枝菌酸合成中的特定作用，并确定其在结核分枝杆菌发病机制中的作用。

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis is responsible for more human deaths than any other single infectious agent and imposes a considerable social and economic toll on a global scale. Adult pulmonary tuberculosis is notoriously difficult to control, requiring extended treatments with multiple antibiotics. Lack of compliance with these regimens has encouraged the appearance of multiple drug-resistant strains of M. tuberculosis. Effective control of tuberculosis requires better diagnostic methods, more efficacious vaccines, and better anti-mycobacterial drugs, particularly for treatments of latent and multi-drug resistant infections. Recent advances in mycobacterial genetics and the availability of several whole mycobacterial genome sequences brings considerable promise to the idea that elucidating the fundamental tenets of mycobacterial physiology, metabolism, genetics and structure will lead to novel strategies for controlling mycobacterial infections. Currently, we know little about the molecular basis of the fundamental aspects of such central questions as to why these bacteria grow so slowly, how is their unique cell wall synthesized, and how do mycobacterial cells communicate. Answering these central questions is important to understanding the molecular basis of mycobacterial pathogenesis and how we might intervene in it. Bacteriophages are powerful tools for understanding their bacterial hosts, and this is certainly true for the mycobacteriophages. Mycobacteriophages are partners in an extremely intimate relationship with their hosts; they are not only dependent on the host metabolic machinery for their replication and assembly, but they must also gain entry through a complex and hostile mycobacterial cell wall, and find ways to exit the cell once it is no longer of any use to them. Furthermore, mycobacteriophages may not kill their hosts at all but integrate their DNA into the host chromosome and co-exist peacefully. This project focuses on examining ways in which mycobacteriophages mimic the cellular signaling pathways of the mycobacteria. We have discovered that mycobacteriophage Bxbl integrates into the groEL1 gene, one of two groEL genes in the mycobacteria. Interruption of the groEL1 gene leads to the loss of biofilm maturation, apparently due to the inability to assemble the FAS-II enzyme complex for mycolate synthesis. We propose to elucidate the specific role of GroEL1 in biofilm formation and mycolic acid synthesis, and to determine its role in the pathogenesis of Mycobacterium tuberculosis.