The intracellular agent of Q fever, Coxiella burnetii, alters human alveolar macrophage metabolism and mitochondrial physiology.

Coxiella burnetii, the etiologic agent of Q fever, is a gram-negative intracellular bacterium that infects humans via contaminated aerosols typically while working with livestock. C. burnetii initially targets alveolar macrophages (AMs) to establish a growth niche within a phagolysosome-like compartment termed the Coxiella-containing vacuole (CCV). C. burnetii deploys a type IV secretion system (T4SS) to secrete effector proteins that control host cell functions to benefit the bacterium, orchestrating an immunosuppressive, pro-bacterial environment for replication to high numbers. Although multiple signaling pathways have been characterized in the context of C. burnetii infection, the role of host cell metabolic function in establishing favorable intracellular conditions is undefined. Using a primary human AM model, we show that C. burnetii maintains host oxidative phosphorylation (OXPHOS) at homeostasis in a T4SS-dependent manner. Inhibiting OXPHOS impairs CCV expansion, while preventing glycolysis and fatty acid oxidation does not alter vacuole development. Interestingly, mitochondria are shorter in infected cells, suggesting C. burnetii manipulates mitochondrial function to regulate host metabolism. Finally, endoplasmic reticulum (ER) stress regulates immunosuppressive macrophage activities, and C. burnetii regulates ER stress in a T4SS-dependent manner. Here, we show the involvement of protein kinase R-like endoplasmic reticulum kinase in regulating OXPHOS during infection. Collectively, our results demonstrate that C. burnetii engages human macrophage metabolic processes to establish a replication niche.IMPORTANCECoxiella burnetii causes human Q fever and is a potential bioterrorism threat. In humans, C. burnetii evades host cell killing and establishes a prolonged replication cycle within AMs, which is a critical step toward presentation of acute or chronic disease symptoms. While macrophage metabolism fuels antibacterial activity, we identified key metabolic processes that C. burnetii manipulates to sustain a pro-bacterial growth niche. Currently, few infection models capture C. burnetii interaction with disease-relevant human cells. Here, we used the established primary human AM infection system to characterize bacterial modulation of macrophage metabolism. Our findings advance understanding of C. burnetii-AM interactions and lay the foundation for future therapeutic exploration.