Intracellular Salmonella hijacks the mitochondrial citrate carrier to evade host oxidative defenses

Chieh-Hua Fu, Yu-Ting Hsu, Shao-Chun Hsu, Nai-Shu Chen, Hsueh-Wen Hu, Ting-Yin Wu, Yi-Jou Huang, Ying-Chu Chen, An-Chi Luo, Yu-Tsung Huang and Shu-Jung Chang ()
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Chieh-Hua Fu: National Taiwan University
Yu-Ting Hsu: National Taiwan University
Shao-Chun Hsu: National Taiwan University
Nai-Shu Chen: National Taiwan University
Hsueh-Wen Hu: National Taiwan University
Ting-Yin Wu: National Taiwan University
Yi-Jou Huang: National Taiwan University
Ying-Chu Chen: National Taiwan University
An-Chi Luo: National Taiwan University
Yu-Tsung Huang: National Taiwan University Hospital
Shu-Jung Chang: National Taiwan University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Intracellular vacuolar pathogens replicate within membrane-bound compartments known as pathogen-containing vacuoles (PCVs). Maintaining the integrity of these vacuoles is essential for creating a permissive niche that supports pathogen survival and proliferation. In this study, we show that Salmonella enterica serovar Typhimurium co-opts the host mitochondrial citrate carrier (CIC) to promote its intracellular replication by detoxifying the Salmonella-containing vacuole (SCV). Loss of CIC significantly impairs Salmonella growth within host cells, as CIC recruitment to SCVs regulates local citrate levels and mitigates the production of reactive oxygen species (ROS), thereby reducing oxidative stress. Mechanistically, we identify the SPI-2 effector SseF as a critical factor that interacts with CIC and the GTPase RAB7, enabling CIC recruitment to the SCV membrane. These findings reveal a previously unrecognized strategy by which an intracellular pathogen hijacks a mitochondrial metabolite transporter to modulate the vacuolar environment and evade host antimicrobial defenses. Notably, pharmacological inhibition of CIC sensitizes Salmonella to host immune pressures, highlighting CIC as a potential target for host-directed antimicrobial therapy.

Date: 2025
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DOI: 10.1038/s41467-025-64779-z

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