Adhvaryu Het, Huang Lu, Long Carrie M, Voth Daniel E
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Bacterial Immunology and Pathogenesis Unit, Laboratory of Bacteriology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
mBio. 2025 Aug 18:e0143625. doi: 10.1128/mbio.01436-25.
, 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.
伯纳特立克次氏体是Q热的病原体，是一种革兰氏阴性细胞内细菌，通常在与家畜接触时通过受污染的气溶胶感染人类。它最初靶向肺泡巨噬细胞（AM），在一个称为含柯克斯体空泡（CCV）的吞噬溶酶体样区室中建立生长微环境。它利用IV型分泌系统（T4SS）分泌效应蛋白来控制宿主细胞功能，以利于细菌生长，营造一个免疫抑制、有利于细菌的环境，使其大量繁殖。尽管在伯纳特立克次氏体感染的背景下已经鉴定出多种信号通路，但宿主细胞代谢功能在建立有利的细胞内环境中的作用尚不清楚。我们使用原代人AM模型表明，伯纳特立克次氏体以T4SS依赖的方式维持宿主氧化磷酸化（OXPHOS）的稳态。抑制OXPHOS会损害CCV的扩张，而抑制糖酵解和脂肪酸氧化不会改变空泡的发育。有趣的是，感染细胞中的线粒体较短，这表明伯纳特立克次氏体操纵线粒体功能来调节宿主代谢。最后，内质网（ER）应激调节免疫抑制性巨噬细胞的活性，而伯纳特立克次氏体以T4SS依赖的方式调节ER应激。在这里，我们展示了蛋白激酶R样内质网激酶在感染期间调节OXPHOS中的作用。总的来说，我们的结果表明，伯纳特立克次氏体参与人类巨噬细胞代谢过程以建立复制微环境。重要性：伯纳特立克次氏体可导致人类Q热，是一种潜在的生物恐怖主义威胁。在人类中，它逃避宿主细胞杀伤，并在AMs内建立延长的复制周期，这是出现急性或慢性疾病症状的关键步骤。虽然巨噬细胞代谢为抗菌活性提供能量，但我们确定了伯纳特立克次氏体操纵以维持有利于细菌生长的微环境的关键代谢过程。目前，很少有感染模型能够捕捉到它与疾病相关人类细胞的相互作用。在这里，我们使用已建立的原代人AM感染系统来表征细菌对巨噬细胞代谢的调节。我们的发现推进了对伯纳特立克次氏体与AM相互作用的理解，并为未来的治疗探索奠定了基础。
