Macrophage activation involves metabolic reprogramming to support antimicrobial cellular functions. How these metabolic shifts influence the outcome of infection by intracellular pathogens remains incompletely understood. Mycobacterium tuberculosis (Mtb) modulates host metabolic pathways and utilizes host nutrients, including cholesterol and fatty acids, to survive within macrophages. We found that intracellular growth of Mtb depends on host fatty acid catabolism: when host fatty acid β-oxidation (FAO) was blocked chemically with trimetazidine, a compound in clinical use, or genetically by deletion of the mitochondrial fatty acid transporter carnitine palmitoyltransferase 2 (CPT2), Mtb failed to grow in macrophages, and its growth was attenuated in mice. Mechanistic studies support a model in which inhibition of FAO generates mitochondrial reactive oxygen species, which enhance macrophage NADPH oxidase and xenophagy activity to better control Mtb infection. Thus, FAO inhibition promotes key antimicrobial functions of macrophages and overcomes immune evasion mechanisms of Mtb.

中文翻译：

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抑制脂肪酸氧化促进巨噬细胞对结核分枝杆菌的控制。

巨噬细胞活化涉及代谢重编程以支持抗菌细胞功能。这些代谢变化如何影响细胞内病原体感染的结果仍然不完全清楚。结核分枝杆菌(Mtb) 调节宿主代谢途径并利用宿主营养物质（包括胆固醇和脂肪酸）在巨噬细胞内存活。我们发现 Mtb 的细胞内生长取决于宿主脂肪酸的分解代谢：当宿主脂肪酸 β-氧化 (FAO) 被临床使用的化合物曲美他嗪化学阻断，或通过线粒体脂肪酸转运体肉碱棕榈酰转移酶 2 的缺失而遗传阻断时。 CPT2)，Mtb 未能在巨噬细胞中生长，其在小鼠中的生长减弱。机制研究支持一个模型，在该模型中，FAO 的抑制会产生线粒体活性氧，从而增强巨噬细胞 NADPH 氧化酶和异体吞噬活性，从而更好地控制 Mtb 感染。因此，FAO 抑制促进了巨噬细胞的关键抗菌功能并克服了 Mtb 的免疫逃避机制。