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。它比任何其他细菌造成的死亡都多，每年在与人类免疫缺陷病毒(HIV)的致命协同作用中夺走约150万人的生命，导致1000万儿童成为这种疾病的孤儿。目前，抗击结核病的药物和疫苗的合理设计受到对细菌生物学的基本了解的限制。结核分枝杆菌在人类宿主中以多个亚群的形式存在，这种适应需要基因表达的显著和适当的变化。基因表达是一个多步骤的过程，但直到最近，对结核分枝杆菌的研究一直只集中在第一步，这在很大程度上受蛋白质因素的调节。然而，很明显，新的和完全不同的非蛋白质调节因子，即所谓的小RNA(SRNAs)，在所有细菌的应激反应中发挥着重要作用。在致病细菌(即病原体)的情况下，这些sRNA在适应恶劣的宿主环境中发挥着关键作用。在最初的步骤发生后，sRNA能够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件以及各种效应分子，如调节剂和分泌的因子，以干扰宿主对入侵病原体的防御。该项目旨在研究在感染过程中高表达的特定结核分枝杆菌sRNA，因此可能对宿主适应和疾病的发展(发病机制)具有重要意义。通过人工操纵单个sRNA的水平，我们将能够检测到哪些基因和分子可能受到这些调节因子的影响，因此涉及哪些细胞机制。然而，我们将不仅能够确定sRNAs在发病机制中扮演什么角色。该项目还将在阐明结核分枝杆菌基因表达和代谢调控等基本分子机制方面具有更广泛的意义，最终将使我们更好地了解该细菌，并导致开发新的结核病干预策略。

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.