{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T01:12:05Z","timestamp":1788484325843,"version":"build-2803163510"},"reference-count":69,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2025,9,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Coxiella burnetii<\/jats:italic>\n                      , the etiologic agent of Q fever, is a gram-negative intracellular bacterium that infects humans via contaminated aerosols typically while working with livestock.\n                      <jats:italic toggle=\"yes\">C. burnetii<\/jats:italic>\n                      initially targets alveolar macrophages (AMs) to establish a growth niche within a phagolysosome-like compartment termed the\n                      <jats:italic toggle=\"yes\">Coxiella<\/jats:italic>\n                      -containing vacuole (CCV).\n                      <jats:italic toggle=\"yes\">C. burnetii<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">C. burnetii<\/jats:italic>\n                      infection, the role of host cell metabolic function in establishing favorable intracellular conditions is undefined. Using a primary human AM model, we show that\n                      <jats:italic toggle=\"yes\">C. burnetii<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">C. burnetii<\/jats:italic>\n                      manipulates mitochondrial function to regulate host metabolism. Finally, endoplasmic reticulum (ER) stress regulates immunosuppressive macrophage activities, and\n                      <jats:italic toggle=\"yes\">C. burnetii<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">C. burnetii<\/jats:italic>\n                      engages human macrophage metabolic processes to establish a replication niche.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        <jats:italic toggle=\"yes\">Coxiella burnetii<\/jats:italic>\n                        causes human Q fever and is a potential bioterrorism threat. In humans,\n                        <jats:italic toggle=\"yes\">C. burnetii<\/jats:italic>\n                        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\n                        <jats:italic toggle=\"yes\">C. burnetii<\/jats:italic>\n                        manipulates to sustain a pro-bacterial growth niche. Currently, few infection models capture\n                        <jats:italic toggle=\"yes\">C. burnetii<\/jats:italic>\n                        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\n                        <jats:italic toggle=\"yes\">C. burnetii<\/jats:italic>\n                        -AM interactions and lay the foundation for future therapeutic exploration.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01436-25","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T12:00:27Z","timestamp":1755518427000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["The intracellular agent of Q fever,\n                    <i>Coxiella burnetii<\/i>\n                    , alters human alveolar macrophage metabolism and mitochondrial physiology"],"prefix":"10.1128","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4385-1318","authenticated-orcid":true,"given":"Het","family":"Adhvaryu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00xcryt71","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Arkansas for Medical Sciences","place":["Little Rock, USA"]},{"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}],"name":"Bacterial Immunology and Pathogenesis Unit, Laboratory of Bacteriology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health","place":["Hamilton, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7820-2177","authenticated-orcid":true,"given":"Lu","family":"Huang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00xcryt71","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Arkansas for Medical Sciences","place":["Little Rock, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5030-975X","authenticated-orcid":true,"given":"Carrie M.","family":"Long","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}],"name":"Bacterial Immunology and Pathogenesis Unit, Laboratory of Bacteriology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health","place":["Hamilton, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7631-7827","authenticated-orcid":true,"given":"Daniel E.","family":"Voth","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00xcryt71","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of Arkansas for Medical Sciences","place":["Little Rock, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00291-21"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.020"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2007.00901.x"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/tbed.13505"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12879-024-09484-w"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.70283"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.70283"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.onehlt.2023.100667"},{"key":"e_1_3_3_10_2","volume-title":"Q fever","author":"Patil SM","year":"2024","unstructured":"Patil SM, Regunath H. 2024. 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