Fabrik Ivo, Spidlova Petra, Prchal Lukas, Fabrikova Daniela, Viduka Ina, Marecic Valentina, Filimonenko Vlada, Sleha Radek, Vajrychova Marie, Kupcik Rudolf, Soukup Ondrej, Rousar Tomas, Härtlova Anetta, Santic Marina, Stulik Jiri
Biomedical Research Center, University Hospital Hradec Kralove, 500 05 Hradec Kralove, Czechia.
Department of Molecular Pathology and Biology, Military Faculty of Medicine, University of Defence, 500 01 Hradec Kralove, Czechia.
Sci Adv. 2025 Aug 29;11(35):eadu6271. doi: 10.1126/sciadv.adu6271.
Dendritic cells (DCs) hijacked by intracellular bacteria contribute to pathogen dissemination and immunopathology. How bacteria achieve DC subversion remains largely unknown. Here, we describe the mechanism used by tularemia agent exploiting host mitochondrial anaplerosis. Shortly after internalization, associates with DC mitochondria, which leads to the rapid repurposing of their oxidative metabolism for production of mitochondrial reactive oxygen species (mtROS). Mitochondrial metabolic rewiring is orchestrated by the intramitochondrial signaling mediated by protein acetylation and involves switching to glutamate as the primary substrate for DC tricarboxylic acid cycle. Rather than killing the bacterium, glutamate-fueled mtROS production activates p38-dependent proinflammatory gene expression. Blocking of glutamate utilization prevents DC activation and bacterial dissemination and alleviates inflammation in vivo. Our findings underscore the importance of metabolic plasticity in antibacterial DC response and open up potential avenues for therapies targeting host metabolism.
被细胞内细菌劫持的树突状细胞（DCs）会促进病原体传播和免疫病理反应。细菌如何实现对DC的颠覆在很大程度上仍不清楚。在此，我们描述了土拉菌病病原体利用宿主线粒体间变途径的机制。内化后不久， 与DC线粒体结合，这导致其氧化代谢迅速重新定向，以产生线粒体活性氧（mtROS）。线粒体代谢重排由蛋白质乙酰化介导的线粒体内信号传导协调，并涉及切换到谷氨酸作为DC三羧酸循环的主要底物。由谷氨酸驱动的mtROS产生不是杀死细菌，而是激活p38依赖的促炎基因表达。阻断谷氨酸利用可防止DC激活和细菌传播，并减轻体内炎症。我们的发现强调了代谢可塑性在抗细菌DC反应中的重要性，并为靶向宿主代谢的治疗开辟了潜在途径。 （注：原文中“ associates with DC mitochondria”前缺少主语，翻译时保留了原文的不完整性）
