{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T21:46:55Z","timestamp":1790200015770,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1010809","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T00:00:00Z","timestamp":1663200000000}}],"reference-count":176,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2022,9,2]],"date-time":"2022-09-02T00:00:00Z","timestamp":1662076800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MFE-17117"],"award-info":[{"award-number":["MFE-17117"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 AI 101171"],"award-info":[{"award-number":["R01 AI 101171"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p><jats:italic>Acinetobacter baumannii<\/jats:italic> is an opportunistic pathogen and an emerging global health threat. Within healthcare settings, major presentations of <jats:italic>A<\/jats:italic>. <jats:italic>baumannii<\/jats:italic> include bloodstream infections and ventilator-associated pneumonia. The increased prevalence of ventilated patients during the COVID-19 pandemic has led to a rise in secondary bacterial pneumonia caused by multidrug resistant (MDR) <jats:italic>A<\/jats:italic>. <jats:italic>baumannii<\/jats:italic>. Additionally, due to its MDR status and the lack of antimicrobial drugs in the development pipeline, the World Health Organization has designated carbapenem-resistant <jats:italic>A<\/jats:italic>. <jats:italic>baumannii<\/jats:italic> to be its priority critical pathogen for the development of novel therapeutics. To better inform the design of new treatment options, a comprehensive understanding of how the host contains <jats:italic>A<\/jats:italic>. <jats:italic>baumannii<\/jats:italic> infection is required. Here, we investigate the innate immune response to <jats:italic>A<\/jats:italic>. <jats:italic>baumannii<\/jats:italic> by assessing the impact of infection on host gene expression using NanoString technology. The transcriptional profile observed in the <jats:italic>A<\/jats:italic>. <jats:italic>baumannii<\/jats:italic> infected host is characteristic of Gram-negative bacteremia and reveals expression patterns consistent with the induction of nutritional immunity, a process by which the host exploits the availability of essential nutrient metals to curtail bacterial proliferation. The gene encoding for lipocalin-2 (<jats:italic>Lcn2<\/jats:italic>), a siderophore sequestering protein, was the most highly upregulated during <jats:italic>A<\/jats:italic>. <jats:italic>baumannii<\/jats:italic> bacteremia, of the targets assessed, and corresponds to robust LCN2 expression in tissues. <jats:italic>Lcn2<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> mice exhibited distinct organ-specific gene expression changes including increased transcription of genes involved in metal sequestration, such as <jats:italic>S100A8<\/jats:italic> and <jats:italic>S100A9<\/jats:italic>, suggesting a potential compensatory mechanism to perturbed metal homeostasis. <jats:italic>In vitro<\/jats:italic>, LCN2 inhibits the iron-dependent growth of <jats:italic>A<\/jats:italic>. <jats:italic>baumannii<\/jats:italic> and induces iron-regulated gene expression. To elucidate the role of LCN2 in infection, WT and <jats:italic>Lcn2<\/jats:italic><jats:sup>-\/-<\/jats:sup> mice were infected with <jats:italic>A<\/jats:italic>. <jats:italic>baumannii<\/jats:italic> using both bacteremia and pneumonia models. LCN2 was not required to control bacterial growth during bacteremia but was protective against mortality. In contrast, during pneumonia <jats:italic>Lcn2<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> mice had increased bacterial burdens in all organs evaluated, suggesting that LCN2 plays an important role in inhibiting the survival and dissemination of <jats:italic>A<\/jats:italic>. <jats:italic>baumannii<\/jats:italic>. The control of <jats:italic>A<\/jats:italic>. <jats:italic>baumannii<\/jats:italic> infection by LCN2 is likely multifactorial, and our results suggest that impairment of iron acquisition by the pathogen is a contributing factor. Modulation of LCN2 expression or modifying the structure of LCN2 to expand upon its ability to sequester siderophores may thus represent feasible avenues for therapeutic development against this pathogen.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010809","type":"journal-article","created":{"date-parts":[[2022,9,2]],"date-time":"2022-09-02T17:43:58Z","timestamp":1662140638000},"page":"e1010809","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":21,"title":["Lipocalin-2 is an essential component of the innate immune response to Acinetobacter baumannii infection"],"prefix":"10.1371","volume":"18","author":[{"given":"Jessica R.","family":"Sheldon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren E.","family":"Himmel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dillon E.","family":"Kunkle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Monteith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. Nichole","family":"Maloney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5094-8105","authenticated-orcid":true,"given":"Eric P.","family":"Skaar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,9,2]]},"reference":[{"key":"ppat.1010809.ref001","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1099\/00207713-36-2-228","article-title":"Taxonomy of the genus Acinetobacter with the recognition of Acinetobacter baumannii sp. nov., Acinetobacter haemolyticus sp. nov., Acinetobacter johnsonii sp. nov., and Acinetobacter junii sp. nov. and emended descriptio","volume":"36","author":"PJM Bouvet","year":"1986","journal-title":"Int J Syst Bacteriol"},{"key":"ppat.1010809.ref002","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1007\/s10096-007-0365-6","article-title":"Community-acquired Acinetobacter infections","volume":"26","author":"ME Falagas","year":"2007","journal-title":"Eur J Clin Microbiol Infect Dis"},{"key":"ppat.1010809.ref003","doi-asserted-by":"crossref","first-page":"ofy044","DOI":"10.1093\/ofid\/ofy044","article-title":"Severe community-acquired pneumonia due to Acinetobacter baumannii in North America: Case report and review of the literature","volume":"5","author":"DP Serota","year":"2018","journal-title":"Open Forum Infect Dis."},{"key":"ppat.1010809.ref004","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1586\/14787210.2015.1025055","article-title":"Community-acquired Acinetobacter baumannii: Clinical characteristics, epidemiology and pathogenesis","volume":"13","author":"C Dexter","year":"2015","journal-title":"Expert Rev Anti Infect Ther"},{"key":"ppat.1010809.ref005","doi-asserted-by":"crossref","first-page":"e000306","DOI":"10.1099\/mgen.0.000306","article-title":"Emergence, molecular mechanisms and global spread of carbapenem-resistant Acinetobacter baumannii","volume":"5","author":"M Hamidian","year":"2019","journal-title":"Microb Genomics"},{"key":"ppat.1010809.ref006","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1038\/nrmicro1789","article-title":"An increasing threat in hospitals: multidrug-resistant Acinetobacter baumannii","volume":"5","author":"L Dijkshoorn","year":"2007","journal-title":"Nat Rev Microbiol"},{"key":"ppat.1010809.ref007","doi-asserted-by":"crossref","first-page":"3471","DOI":"10.1128\/AAC.01464-06","article-title":"Global challenge of multidrug-resistant Acinetobacter baumannii","volume":"51","author":"F Perez","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"key":"ppat.1010809.ref008","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1097\/MCC.0000000000000337","article-title":"Emergence of antimicrobial resistance among Acinetobacter species: A global threat","volume":"22","author":"NM Clark","year":"2016","journal-title":"Curr Opin Crit Care"},{"key":"ppat.1010809.ref009","first-page":"1","volume-title":"Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics","author":"WHO Press","year":"2017"},{"key":"ppat.1010809.ref010","unstructured":"CDC. 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