The intracellular agent of Q fever, <i>Coxiella burnetii</i> , alters human alveolar macrophage metabolism and mitochondrial physiology

<i>Coxiella burnetii</i>, the etiologic agent of Q fever, is a gram-negative intracellular bacterium that infects humans via contaminated aerosols typically while working with livestock. <i>C. burnetii</i> initially targets alveolar macrophages (AMs) to establish a growth niche within a phagolysosome-like compartment termed the <i>Coxiella</i>-containing vacuole (CCV). <i>C. burnetii</i> 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 <i>C. burnetii</i> infection, the role of host cell metabolic function in establishing favorable intracellular conditions is undefined. Using a primary human AM model, we show that <i>C. burnetii</i> 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 <i>C. burnetii</i> manipulates mitochondrial function to regulate host metabolism. Finally, endoplasmic reticulum (ER) stress regulates immunosuppressive macrophage activities, and <i>C. burnetii</i> 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 <i>C. burnetii</i> engages human macrophage metabolic processes to establish a replication niche.IMPORTANCE<i>Coxiella burnetii</i> causes human Q fever and is a potential bioterrorism threat. In humans, <i>C. burnetii</i> 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 <i>C. burnetii</i> manipulates to sustain a pro-bacterial growth niche. Currently, few infection models capture <i>C. burnetii</i> 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 <i>C. burnetii</i>-AM interactions and lay the foundation for future therapeutic exploration.