Chewing the fat - Long chain fatty acid uptake and assimilation in Mycobacterium tuberculosis.

由于三分之一的人类受到感染，每年约有800万新发病例，超过200万人死亡，结核病仍然是一个主要的全球健康问题;它也是英国许多城市中心如莱斯特的一个重大问题。我们迫切需要更好的诊断方法、更好的治疗方法和更好的疫苗。我们对结核病的病原菌结核分枝杆菌（Mtb）的了解，大部分来自于在实验室培养这种细菌。然而，总是有一个危险，生物体？我们观察到结核病患者的痰液样本中结核分枝杆菌细胞经常含有脂肪滴，但这些脂肪滴很难在实验室培养中显示出来。我们已经研究了几年的代谢过程中负责液滴形成结核分枝杆菌及其亲属。这些生物体对脂肪和相关化合物的需求最高，以制造它们的细胞涂层。人们普遍认为，这种涂层对结核分枝杆菌抵抗人类免疫系统攻击、引起疾病和抵抗许多抗生素的方式至关重要。我们认为，液滴反映了Mtb加工脂肪的重要性，相关的代谢过程是其在感染期间生长和存活的核心。在这项研究中，我们的目的是找出Mtb如何将外部资源加工成脂肪滴。因为许多结核分枝杆菌细胞生长在称为巨噬细胞的吞噬性人类免疫细胞内，所以我们的大部分工作将基于在实验室模型巨噬细胞系统中培养生物体。我们将综合运用遗传学、生物化学和显微镜技术。其中最后一个将是特别有利的，可能在随后的项目中，我们调查我们阐明的代谢过程是否与Mtb在人类感染样本中的行为有关。我们研究的一个重要部分将涉及找出干扰脂肪滴系统如何影响Mtb在巨噬细胞内的生长和存活。我们认为，仔细调节的脂肪滴系统可能是非常重要的结核分枝杆菌，该项目将为我们提供不仅有更好的了解结核病，但也有重要的机会，开发新的治疗方法。

With one third of humanity infected, roughly 8 million new cases every year and over 2 million deaths, tuberculosis remains a major global health problem; it is also a significant problem in many urban centres in the UK such as Leicester. We urgently need better diagnostics, better treatments and better vaccines.Most of what we know about the bacterium responsible for tuberculosis, Mycobacterium tuberculosis (Mtb), derives from growing the bug in laboratory cultures. However, there is always a danger that the organism?s behaviour may be different in test tubes compared to its behaviour in humans.We have observed that Mtb cells frequently contain fat droplets in sputum samples from tuberculosis patients but that these droplets are difficult to demonstrate in laboratory cultures. We have been studying the metabolic process responsible for droplet formation in Mtb and its relatives for several years. These organisms have highest demand to make fats and related compounds to manufacture their cell coating. It is widely believed that this coating is critical to the way Mtb survives against the attack of the human immune system, causes disease and resists many antibiotics. We believe that the droplets reflect the importance to Mtb of processing fats and that the related metabolic processes are central to its growth and survival during infection.In this study we aim find out how Mtb processes external resources into and out of fat droplets. Because many Mtb cells grow inside the phagocytic human immune cells called macrophages much of our work will be based on growing the organism in a laboratory model macrophage system. We will use a combination of genetic, biochemical and microscope-based techniques. The last of these will be particularly advantageous when, probably in a subsequent project, we investigate whether the metabolic processes we elucidate are relevant to how Mtb behaves in samples from human infections.A significant part of our study will be concerned with finding out how interfering with the fat droplet system affects Mtb growth and survival inside macrophages. We argue that careful regulation of the fat droplet system may be very important to Mtb and that this project will provide us not only with a better understanding of tuberculosis but also with important opportunities to develop new treatments.