The role of host-derived lipids in Mycobacterium tuberculosis infection

结核分枝杆菌（Mycobacterium tuberculosis）是一种全球性的杀手，每年导致超过100万人死于结核病（TB）。因此，它是人类健康的一个主要负担。为了减少结核病的致命影响，我们需要更好地了解M。结核病适应其代谢，以便在人类宿主遇到的可变环境中生存;这将有助于我们设计更好的治疗和控制结核病的方法。所有细胞都需要对环境变化做出反应，例如酸性pH值，这是胃内遇到的一种情况，以及吞噬分枝杆菌的巨噬细胞。对酸的反应已经在大肠杆菌、霍乱弧菌和幽门螺杆菌等细菌中进行了广泛的研究，这些细菌都遇到了胃的极酸性pH值（pH 2-3）。相比之下，关于细菌病原体如何在人体细胞内生存的信息很少，如M。结核病，生存和复制细胞内的酸性空泡，如巨噬细胞。M.结核菌的pH范围为6.2至4.5，这取决于巨噬细胞的活化状态。我们可以研究细菌如何在实验室的培养瓶中对pH值的变化做出反应并存活下来，以及在培养的巨噬细胞中识别帮助它们存活的细菌因子。改变M.结核病代谢是在环境变化中生存的一种方式，干扰这些过程是治疗结核病的一种有吸引力的方法。我们已经确定了一种酶cAMP依赖性赖氨酸乙酰转移酶（Rv 0998，KATmt）参与酸存活，并根据我们的初步数据，我们假设，KATmt在代谢适应M。结核分枝杆菌细胞内生命的关键部分。为了解决这一假设，我们建议研究KATmt在重组结核分枝杆菌代谢中的作用。结核病在整个细胞水平。为了实现这一目标，我们的目标是：1。利用M.结核病KATmt，以确定代谢途径KATmt以及如何调节。确定KATmt活性的底物，这可能代表新的和有吸引力的药物靶点。2.使用生物能量学和代谢组学来确定KATmt在宿主巨噬细胞代谢组重塑中的作用。M.结核病操纵其宿主细胞，为其生存和复制创造更有利的环境，了解它是如何做到这一点的，是找到新的干预措施的关键。3.我们将比较KATmt突变株在小鼠结核病模型中的表现，与亲本菌株和补充菌株相比，寻找与感染相关的细菌存活变化和宿主脂质变化，以这种方式，我们将阐明KATmt介导M耐药性的机制。结核杆菌不仅通过改变自身的代谢，而且通过操纵宿主巨噬细胞的脂质代谢来抵抗感染过程中遇到的酸性应激。结核病发病机制，开辟了新的途径，小分子干预。

The bacteria Mycobacterium tuberculosis is a global killer causing over a million deaths from tuberculosis (TB) every year. It is therefore a major burden to human health. To reduce the deadly impact of TB, we need a better understanding of the strategies used by M. tuberculosis to adapt its metabolism in order to survive in the variable environments encountered in the human host; this will help us design better ways to treat and control TB. All cells need to respond to environmental changes such as acidic pH, a condition encountered within the stomach as well as the macrophages that engulf mycobacteria. Responses to acid have been studied extensively in bacteria such as Escherichia coli, Vibrio cholerae, and Helicobacter pylori, that all encounter the extremely acidic pH (pH 2-3) of the stomach. In contrast, there is little information on how bacterial pathogens that can live inside human cells, like M. tuberculosis, survive and replicate within acid vacuoles inside cells like macrophages. The pH of the macrophage compartment in which M. tuberculosis resides ranges from pH 6.2 to 4.5, depending on the activation state of the macrophage. We can study how bacteria respond to and survive changes in pH in culture flasks in the laboratory, as well as in cultured macrophages to identify bacterial factors that help them survive. Changing M. tuberculosis metabolism is one way to survive changes in the environment and interfering with these processes presents an attractive method for treating TB. We have identified an enzyme cAMP-dependant-lysine acetyl transferase (Rv0998, KATmt) involved in acid survival, and based on our preliminary data we hypothesize that KATmt plays a key role in the metabolic adaptation of M. tuberculosis to intracellular life a key part of M. tuberculosis pathogenesis.To address this hypothesis, we propose to study the role of KATmt in rewiring the metabolism of M. tuberculosis at a whole cell level. To achieve this goal our objectives are to:1. Use genetic mutants of M. tuberculosis KATmt to identify the metabolic pathways KATmt and how this is regulated. Identify substrates for KATmt activity, which may represent new and attractive drug targets. 2. Use bioenergetics and metabolomics to determine the role KATmt plays in host macrophage metabolome remodelling. M. tuberculosis manipulates its host cell to generate a more favourable environment for its survival and replication, and understanding how it does this is key to finding new interventions. 3. We will compare how the KATmt mutant behave in the mouse model of TB, compared to the parental and complemented strains, looking for changes in bacterial survival and changes in host lipids associated with infection.In this way, we will elucidate the mechanisms by which KATmt mediates the resistance of M. tuberculosis to the acidic stress encountered during infection not only by altering its own metabolism, but also by manipulating host macrophage lipid metabolism Overall, this will identify and validate key pathways in M. tuberculosis pathogenesis, opening up new avenues for small molecule interventions.