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 Francisella tularensis exploiting host mitochondrial anaplerosis. Shortly after internalization, Francisella 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.

Biomedical Research Center University Hospital Hradec Kralove 500 05 Hradec Kralove Czechia

Department of Biological and Biochemical Sciences Faculty of Chemical Technology University of Pardubice 532 10 Pardubice Czechia

Department of Environmental Health Teaching Institute of Public Health of Primorje Gorski Kotar County Rijeka Croatia

Department of Epidemiology Military Faculty of Medicine University of Defence 500 01 Hradec Kralove Czechia

Department of Microbiology and Parasitology Faculty of Medicine University of Rijeka 51000 Rijeka Croatia

Department of Molecular Pathology and Biology Military Faculty of Medicine University of Defence 500 01 Hradec Kralove Czechia

Electron Microscopy Core Facility Institute of Molecular Genetics Czech Academy of Sciences 142 20 Prague Czechia

Institute of Medical Microbiology and Hygiene Medical Center University of Freiburg Faculty of Medicine 79104 Freiburg Germany

Laboratory of Biology of the Cell Nucleus Institute of Molecular Genetics Czech Academy of Sciences 142 20 Prague Czechia

Wallenberg Centre for Molecular and Translational Medicine Department of Microbiology and Immunology at Institute of Biomedicine University of Gothenburg 405 30 Gothenburg Sweden

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