The role of host-derived lipids in Mycobacterium tuberculosis infection

宿主来源的脂质在结核分枝杆菌感染中的作用

• 批准号: MR/W018756/1
• 负责人: Gerald Larrouy-Maumus
• 金额: $ 72.48万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW018756%2F1
• 关键词: role; host; derived; lipids; Mycobacterium

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.

结核分枝杆菌是一种全球杀手，每年导致100多万人死于结核病。因此，它是人类健康的主要负担。为了减少结核病的致命影响，我们需要更好地了解结核分枝杆菌用来调整其新陈代谢的策略，以便在人类宿主遇到的多变环境中生存；这将有助于我们设计更好的方法来治疗和控制结核病。所有细胞都需要对环境变化做出反应，如酸性pH，这是一种在胃内遇到的情况，也是吞噬分枝杆菌的巨噬细胞。对酸的反应在大肠杆菌、霍乱弧菌和幽门螺杆菌等细菌中进行了广泛的研究，这些细菌都会遇到胃的极端酸性pH(pH 2-3)。相比之下，关于结核分枝杆菌等可以生活在人类细胞内的细菌病原体如何在巨噬细胞等细胞内的酸性空泡中生存和复制的信息很少。结核分枝杆菌所在的巨噬细胞隔室的pH值从6.2到4.5不等，这取决于巨噬细胞的激活状态。我们可以研究细菌如何对实验室培养瓶中以及培养的巨噬细胞中的pH变化做出反应并存活下来，以确定帮助它们存活的细菌因素。改变结核分枝杆菌的新陈代谢是在环境变化中生存的一种方式，而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与酸生存有关的cAMP依赖的赖氨酸乙酰转移酶(Rv0998，KATmt)，并根据我们的初步数据假设KATmt在结核分枝杆菌对细胞内生活的代谢适应中发挥关键作用，细胞内生活是结核分枝杆菌致病的关键部分。为了实现这一目标，我们的目标是：1.利用结核分枝杆菌KATmt的基因突变来确定KATmt的代谢途径及其调控方式。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.利用生物能量学和代谢组学研究KATmt在宿主巨噬细胞代谢组重构中的作用。结核分枝杆菌操纵其宿主细胞，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，是找到新干预措施的关键。3.我们将比较KATmt突变体在结核病小鼠模型中的表现，并与亲本和补充菌株进行比较，以寻找细菌存活的变化和与感染相关的宿主血脂的变化。通过这种方式，我们将阐明KATmt不仅通过改变自身的代谢，而且通过整体调控宿主巨噬细胞的脂质代谢来调节结核分枝杆菌对感染过程中遇到的酸性应激的抵抗力的机制，这将识别和验证结核分枝杆菌发病机制中的关键途径，为小分子干预开辟新的途径。

项目成果

Metabolite supplements as a route to enhance clearance of infections

代谢补充剂作为增强感染清除的途径

• DOI: 10.1002/ctd2.159
• 发表时间: 2022
• 期刊: Clinical and Translational Discovery
• 作者: Liu Y

Ion mobility mass spectrometry for the study of mycobacterial mycolic acids.

• DOI: 10.1038/s41598-023-37641-9
• 发表时间: 2023-06-27
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Liu, Yi;Kaffah, Nadhira;Pandor, Sufyan;Sartain, Mark J.;Larrouy-Maumus, Gerald
• 通讯作者: Larrouy-Maumus, Gerald