{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T04:58:08Z","timestamp":1791867488101,"version":"4.3.4"},"reference-count":73,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T00:00:00Z","timestamp":1652832000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["DOC 82 doc.fund"],"award-info":[{"award-number":["DOC 82 doc.fund"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Pneumonia is often elicited by bacteria and can be associated with a severe clinical course, respiratory failure and the need for mechanical ventilation. In the alveolus, type-2-alveolar-epithelial-cells (AECII) contribute to innate immune functions. We hypothesized that AECII actively adapt cellular iron homeostasis to restrict this essential nutrient from invading pathogens \u2013 a defense strategy termed \u2018nutritional immunity\u2019, hitherto mainly demonstrated for myeloid cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We established an <jats:italic>in-vitro<\/jats:italic> infection model using the human AECII-like cell line A549. We infected cells with <jats:italic>Klebsiella pneumoniae<\/jats:italic> (<jats:italic>K. pneumoniae<\/jats:italic>) and <jats:italic>Escherichia coli<\/jats:italic> (<jats:italic>E. coli<\/jats:italic>), two gram-negative bacteria with different modes of infection and frequent causes of hospital-acquired pneumonia. We followed the entry and intracellular growth of these gram-negative bacteria and analyzed differential gene expression and protein levels of key inflammatory and iron metabolism molecules.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Both, <jats:italic>K. pneumoniae<\/jats:italic> and <jats:italic>E. coli<\/jats:italic> are able to invade A549 cells, whereas only <jats:italic>K. pneumoniae<\/jats:italic> is capable of proliferating intracellularly. After peak bacterial burden, the number of intracellular pathogens declines, suggesting that epithelial cells initiate antimicrobial immune effector pathways to combat bacterial proliferation. The extracellular pathogen <jats:italic>E. coli<\/jats:italic> induces an iron retention phenotype in A549 cells, mainly characterized by the downregulation of the pivotal iron exporter ferroportin, the upregulation of the iron importer transferrin-receptor-1 and corresponding induction of the iron storage protein ferritin. In contrast, cells infected with the facultative intracellular bacterium <jats:italic>K. pneumoniae<\/jats:italic> exhibit an iron export phenotype indicated by ferroportin upregulation. This differential regulation of iron homeostasis and the pathogen-specific inflammatory reaction is likely mediated by oxidative stress.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>AECII-derived A549 cells show pathogen-specific innate immune functions and adapt their iron handling in response to infection. The differential regulation of iron transporters depends on the preferential intra- or extracellular localization of the pathogen and likely aims at limiting bacterial iron availability.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2022.875543","type":"journal-article","created":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T05:56:02Z","timestamp":1652853362000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Airway Epithelial Cells Differentially Adapt Their Iron Metabolism to Infection With Klebsiella pneumoniae and Escherichia coli In Vitro"],"prefix":"10.3389","volume":"12","author":[{"given":"Philipp","family":"Grubwieser","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Hilbe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Seifert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Sonnweber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"B\u00f6ck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Theurl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fcnter","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Nairz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e00224","DOI":"10.1128\/mBio.00224-11","article-title":"Interaction of Lipocalin 2, Transferrin, and Siderophores Determines the Replicative Niche of Klebsiella Pneumoniae During Pneumonia","volume":"3","author":"Bachman","year":"2012","journal-title":"mBio"},{"key":"B2","doi-asserted-by":"publisher","first-page":"3309","DOI":"10.1128\/IAI.05114-11","article-title":"Klebsiella Pneumoniae Yersiniabactin Promotes Respiratory Tract Infection Through Evasion of Lipocalin 2","volume":"79","author":"Bachman","year":"2011","journal-title":"Infection Immun."},{"key":"B3","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1183\/09031936.03.00098803","article-title":"Innate Immunity in the Lung: How Epithelial Cells Fight Against Respiratory Pathogens","volume":"23","author":"Bals","year":"2004","journal-title":"Eur. 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