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

全球有三分之一的人受到感染，每年大约有800万新病例，200多万人死亡，结核病仍然是一个主要的全球健康问题；这也是英国许多城市中心的一个严重问题，比如莱斯特。我们迫切需要更好的诊断、更好的治疗和更好的疫苗。我们对结核分枝杆菌（Mycobacterium tuberculosis, Mtb）这种导致结核病的细菌的了解，大部分来自于实验室培养。然而，总有一种危险，那就是有机体？S在试管中的行为与在人体内的行为可能不同。我们观察到结核分枝杆菌细胞在结核病患者的痰样本中经常含有脂肪滴，但这些脂肪滴在实验室培养中很难证实。多年来，我们一直在研究结核分枝杆菌及其近亲中液滴形成的代谢过程。这些生物对制造脂肪和相关化合物以制造细胞外壳的需求最高。人们普遍认为，这种涂层对结核分枝杆菌抵抗人体免疫系统的攻击、引起疾病和抵抗许多抗生素的方式至关重要。我们认为，这些液滴反映了脂肪加工对结核分枝杆菌的重要性，以及相关的代谢过程对其感染期间的生长和存活至关重要。在这项研究中，我们的目标是找出结核分枝杆菌是如何将外部资源转化为脂肪滴的。因为许多结核分枝杆菌细胞生长在被称为巨噬细胞的吞噬性人体免疫细胞内，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。我们将结合使用基因、生化和显微镜技术。当我们在随后的项目中研究我们阐明的代谢过程是否与人类感染样本中的结核分枝杆菌行为有关时，最后一项将特别有利。我们研究的一个重要部分将关注于发现干扰脂肪滴系统如何影响巨噬细胞内Mtb的生长和存活。我们认为，仔细调节脂肪滴系统可能对结核分枝杆菌非常重要，该项目不仅将为我们更好地了解结核病，而且为开发新的治疗方法提供重要机会。

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.