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For over 20 years, studies have repeatedly demonstrated that the major siderophore pyoverdine is an important virulence factor for\n              <jats:italic>P. aeruginosa<\/jats:italic>\n              in invertebrate and mammalian hosts\n              <jats:italic>in vivo<\/jats:italic>\n              . Despite its physiological significance, an\n              <jats:italic>in vitro<\/jats:italic>\n              , mammalian cell culture model that can be used to characterize the impact and molecular mechanisms of pyoverdine-mediated virulence has only been developed very recently. In this study, we adapt a previously-established, murine macrophage-based model to use human bronchial epithelial (16HBE) cells. We demonstrate that conditioned medium from\n              <jats:italic>P. aeruginosa<\/jats:italic>\n              induced rapid 16HBE cell death through the pyoverdine-dependent secretion of cytotoxic rhamnolipids. Genetic or chemical disruption of pyoverdine biosynthesis decreased rhamnolipid production and mitigated cell death. Consistent with these observations, chemical depletion of lipids or genetic disruption of rhamnolipid biosynthesis abrogated the toxicity of the conditioned medium. Furthermore, we also examine the effects of exposure to purified pyoverdine on 16HBE cells. While pyoverdine accumulated within cells, it was largely sequestered within early endosomes, resulting in minimal cytotoxicity. More membrane-permeable iron chelators, such as the siderophore pyochelin, decreased epithelial cell viability and upregulated several pro-inflammatory genes. However, pyoverdine potentiated these iron chelators in activating pro-inflammatory pathways. Altogether, these findings suggest that the siderophores pyoverdine and pyochelin play distinct roles in virulence during acute\n              <jats:italic>P. aeruginosa<\/jats:italic>\n              lung infection.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              Multidrug-resistant\n              <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n              is a versatile bacterium that frequently causes lung infections. This pathogen is life-threatening to mechanically-ventilated patients in intensive care units and is a debilitating burden for individuals with cystic fibrosis. However, the role of\n              <jats:italic>P. aeruginosa<\/jats:italic>\n              virulence factors and their regulation during infection are not fully understood. Previous murine lung infection studies have demonstrated that the production of siderophores (e.g., pyoverdine and pyochelin) is necessary for full\n              <jats:italic>P. aeruginosa<\/jats:italic>\n              virulence. In this report, we provide further mechanistic insight into this phenomenon. We characterize distinct and novel ways these siderophores contribute to virulence using an\n              <jats:italic>in vitro<\/jats:italic>\n              human lung epithelial cell culture model.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/spectrum.03693-23","type":"journal-article","created":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T05:00:29Z","timestamp":1707109229000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":11,"title":["<i>In vitro<\/i>\n            lung epithelial cell model reveals novel roles for\n            <i>Pseudomonas aeruginosa<\/i>\n            siderophores"],"prefix":"10.1128","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5314-0961","authenticated-orcid":true,"given":"Donghoon","family":"Kang","sequence":"first","affiliation":[{"name":"Department of BioSciences, Rice University, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of BioSciences, Rice University, Houston, Texas, USA"},{"name":"Department of Bioengineering, Rice University, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1537-4967","authenticated-orcid":true,"given":"Natalia V.","family":"Kirienko","sequence":"additional","affiliation":[{"name":"Department of BioSciences, Rice University, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000000510"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.15.2.194-222.2002"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12890-016-0339-5"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12275-014-4068-2"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1097\/MCP.0b013e328321861a"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-540-75418-3_5"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pupt.2007.12.001"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201705-1043SO"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.2174\/0929867321666141011194624"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.1999.01586.x"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2013.00075"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2006.11.004"},{"key":"e_1_3_3_14_2","first-page":"2509","article-title":"Iron acquisition from transferrin and lactoferrin by Pseudomonas aeruginosa pyoverdin","volume":"143","author":"Xiao R","year":"1997","unstructured":"Xiao R, Kisaalita WS. 1997. 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