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

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