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The human respiratory tract is a common anatomical site for viral-bacterial co-infections, where primary viral infections predispose to secondary bacterial infections, leading to increased morbidity and mortality. Additionally, co-infections are disproportionately prevalent in people with chronic lung diseases, such as chronic obstructive pulmonary disease and cystic fibrosis. We previously reported that primary viral infections and antiviral interferon (IFN) signaling stimulate\n                      <jats:italic toggle=\"yes\">Pseudomonas aeruginosa<\/jats:italic>\n                      biofilm formation on airway epithelial cells (AECs). IFN signaling induces aerobic glycolysis in AECs and generates lactate as a cellular byproduct. Given that innate immune systems play an integral role in co-infection dynamics, we investigated the role of host-secreted metabolites (i.e., lactate) on innate immune cell activity during respiratory co-infections. We found that exposure to the apical secretions from IFN\u03b2-treated AECs significantly compromised macrophage antibacterial activity, with the soluble metabolite lactate playing an important role. Macrophages used monocarboxylate transporters (MCTs) and G-protein receptors to transport and\/or sense lactate, respectively, and this exposure to lactate diminished their bacterial-killing activity in a time exposure-dependent manner. Lactate exposure particularly reprogrammed macrophage cellular metabolism toward a metabolically uncoupled state by increasing oxidative phosphorylation, fatty acid oxidation, and downregulating the proinflammatory antimicrobial functions. Collectively, these findings provide insights into metabolites as complex regulators of trans-kingdom interactions and epithelial-macrophage crosstalk during respiratory co-infections.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/iai.00409-26","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T13:01:07Z","timestamp":1791810067000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Host-secreted lactate during respiratory viral infection diminishes macrophage antibacterial activity through metabolic reprogramming"],"prefix":"10.1128","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0764-0540","authenticated-orcid":true,"given":"Sadia","family":"Sultana","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College","place":["Hanover, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Walsh","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College","place":["Hanover, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4767-6238","authenticated-orcid":true,"given":"Jennifer M.","family":"Bomberger","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College","place":["Hanover, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","published-online":{"date-parts":[[2026,10,12]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-37162-w"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1516979113"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/00001432-200406000-00003"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.inf.0000108197.81270.35"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.00295-22"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198412273112602"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00083-16"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2016.11.003"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/msphere.00984-21"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1177\/2049936119865798"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.03067"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00514"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2015-207020"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.00476-23"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01452-1"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-019-0315-0"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-021-00480-w"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.4RU0620-245R"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202004-0991OC"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep38532"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.00863-23"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2016.10.011"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011719"},{"key":"e_1_3_3_25_2","first-page":"518","article-title":"Metabolic alterations in cancer. 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