Immunobiology of Infection Unit, Institut Pasteur, INSERM U1221, Paris, France.
Université de Paris, Sorbonne Paris Cité, Paris, France.
Immunol Rev. 2021 May;301(1):84-97. doi: 10.1111/imr.12952. Epub 2021 Feb 8.
While the existence of a special relationship between Mycobacterium tuberculosis (Mtb) and host lipids has long been known, it remains a challenging enigma. It was clearly established that Mtb requires host fatty acids (FAs) and cholesterol to produce energy, build its distinctive lipid-rich cell wall, and produce lipid virulence factors. It was also observed that in infected hosts, Mtb constantly resides in a FA-rich environment that the pathogen contributes to generate by inducing a lipid-laden "foamy" phenotype in host macrophages. These observations and the proximity between lipid droplets and phagosomes containing bacteria within infected macrophages gave rise to the hypothesis that Mtb reprograms host cell lipid metabolism to ensure a continuous supply of essential nutrients and its long-term persistence in vivo. However, recent studies question this principle by indicating that in Mtb-infected macrophages, lipid droplet formation prevents bacterial acquisition of host FAs while supporting the production of FA-derived protective lipid mediators. Further, in vivo investigations reveal discrete macrophage phenotypes linking the FA metabolisms of host cell and intracellular pathogen. Notably, FA storage within lipid droplets characterizes both macrophages controlling Mtb infection and dormant intracellular Mtb. In this review, we integrate findings from immunological and microbiological studies illustrating the new concept that cytoplasmic accumulation of FAs is a metabolic adaptation of macrophages to Mtb infection, which potentiates their antimycobacterial responses and forces the intracellular pathogen to shift into fat-saving, survival mode.
虽然分枝杆菌（Mtb）与宿主脂质之间存在特殊关系早已为人所知，但这仍然是一个具有挑战性的谜。显然，Mtb 需要宿主脂肪酸（FAs）和胆固醇来产生能量，构建其独特的富含脂质的细胞壁，并产生脂质毒力因子。还观察到，在感染宿主中，Mtb 不断存在于富含 FA 的环境中，病原体通过诱导宿主巨噬细胞中富含脂质的“泡沫”表型来产生这种环境。这些观察结果以及脂质滴与感染巨噬细胞中含菌吞噬体之间的接近程度，使得人们假设 Mtb 重新编程宿主细胞脂质代谢，以确保持续供应必需的营养物质，并使其在体内长期存活。然而，最近的研究通过表明在 Mtb 感染的巨噬细胞中，脂质滴的形成阻止了细菌获取宿主 FAs，同时支持了 FA 衍生的保护性脂质介质的产生，对这一原则提出了质疑。此外，体内研究揭示了与宿主细胞和细胞内病原体的 FA 代谢相关的离散巨噬细胞表型。值得注意的是，脂质滴内的 FA 储存特征存在于控制 Mtb 感染的巨噬细胞和休眠的细胞内 Mtb 中。在这篇综述中，我们整合了免疫学和微生物学研究的发现，说明了一个新概念，即细胞质中 FA 的积累是巨噬细胞对 Mtb 感染的一种代谢适应，这增强了它们的抗分枝杆菌反应，并迫使细胞内病原体进入节约脂肪、生存模式。
