The role of small regulatory RNAs in Mycobacterium tuberculosis pathogenesis

结核分枝杆菌仍然是全球健康的主要威胁。它比任何其他细菌都要造成更多的死亡，每年与人类免疫缺陷病毒（HIV）致命的协同作用造成约150万人死亡，使1000万儿童因这种疾病而成为孤儿。目前，由于对结核菌生物学的基本了解有限，阻碍了合理设计防治结核病的药物和疫苗。M.结核病作为多个亚群持续存在于人类宿主中，这是一种需要基因表达发生显著和适当变化的适应。基因表达是一个多步骤的过程，但在M。直到最近，结核病只集中在第一步，这在很大程度上是由蛋白质因子调节的。然而，很明显，新的和完全不同的非蛋白质调节剂，所谓的小RNA（sRNA），在所有细菌的应激反应中起着重要作用。在致病细菌（即病原体）的情况下，这些sRNA在适应不利的宿主环境中起着至关重要的作用。sRNA能够在初始步骤发生后，通过促进或抑制基因表达的下一步，即细菌蛋白质的产生，来改变基因表达的最终结果。这些蛋白质包括细胞的构建模块以及各种效应分子，例如分泌以干扰宿主对入侵病原体的防御的调节剂和因子。本课题旨在对M.结核sRNA在感染过程中高度表达，因此可能在宿主适应和疾病发展（发病机制）中具有重要意义。通过人工操纵单个sRNA的水平，我们将能够检测哪些基因和分子可能受到这些调节因子的影响，从而确定涉及哪些细胞机制。然而，我们不仅能够确定sRNAs在发病机制中发挥的作用。该项目也将在阐明基本的分子机制，如调节M。结核病基因表达和代谢，这将最终为我们提供更好的了解细菌，并导致新的结核病干预策略的发展。

Mycobacterium tuberculosis, remains a major threat to global health. It is responsible for more deaths than any other bacterium and claims around 1.5 million lives every year in a deadly synergy with Human Immunodeficiency Virus (HIV), leaving ten million children orphaned by this disease. Rational design of drugs and vaccines to combat tuberculosis is currently hampered by limitations in basic understanding of the biology of the bacterium. M. tuberculosis persists in the human host as multiple subpopulations, an adaptation that requires significant and appropriate changes in gene expression. Gene expression is a multi-step process, but research in M. tuberculosis has until recently focused on only the first step, which is largely regulated by protein factors. However, it has become evident that novel and quite different non-protein regulators, the so-called small RNAs (sRNAs), play a major role in stress responses in all bacteria. In the case of disease causing bacteria (i.e. pathogens), these sRNAs play a crucial role in the adaptation to hostile host environments. sRNAs are able to modify the final outcome of gene expression after the initial step has taken place, by either promoting or inhibiting the next step in gene expression, that is, the production of bacterial proteins. These proteins include the building blocks of the cell as well as various effector molecules such as regulators and factors that are secreted in order to interfere with the host's defence against the invading pathogen. This project aims at investigating selected M. tuberculosis sRNAs that are highly expressed during infection and therefore might be of importance in host adaptation and development of the disease (pathogenesis). By artificially manipulating the levels of individual sRNAs we will be able to detect which genes and molecules may be affected by these regulators and hence what cellular mechanisms are involved. However, we will not only be able to determine what role the sRNAs play in pathogenesis. This project will also have broader implications in elucidating basic molecular mechanisms such as regulation of M. tuberculosis gene expression and metabolism, which will eventually provide us with a better understanding of the bacterium, and lead to the development of novel intervention strategies for tuberculosis.