{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T22:35:20Z","timestamp":1782772520837,"version":"3.54.5"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,24]],"date-time":"2021-02-24T00:00:00Z","timestamp":1614124800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["5R21HD092934"],"award-info":[{"award-number":["5R21HD092934"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["UO1HL075904"],"award-info":[{"award-number":["UO1HL075904"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008552","name":"Brigham Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008552","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1 HL68111"],"award-info":[{"award-number":["RO1 HL68111"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Angiotensin converting enzyme 2 (ACE2) is the putative functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current literature on the abundance and distribution of ACE2 protein in the human respiratory tract is controversial. We examined the effect of age and lung injury on ACE2 protein expression in rodent and non-human primate (NHP) models. We also examined ACE2 expression in human tissues with and without coronavirus disease 19 (COVID-19). ACE2 expression was detected at very low levels in preterm, but was absent in full-term and adult NHP lung homogenates. This pattern of ACE2 expression contrasted with that of transmembrane protease serine type 2 (TMPRSS2), which was significantly increased in full-term newborn and adult NHP lungs compared to preterm NHP lungs. ACE2 expression was not detected in NHP lungs with cigarette smoke-induced airway disease or bronchopulmonary dysplasia. Murine lungs lacked basal ACE2 immunoreactivity, but responded to hyperoxia, bacterial infection, and allergen exposure with new ACE2 expression in bronchial epithelial cells. In human specimens, robust ACE2 immunoreactivity was detected in ciliated epithelial cells in paranasal sinus specimens, while ACE2 expression was detected only in rare type 2 alveolar epithelial cells in control lungs. In autopsy specimens from patients with COVID-19 pneumonia, ACE2 was detected in rare ciliated epithelial and endothelial cells in the trachea, but not in the lung. There was robust expression of ACE2 expression in F344\/N rat nasal mucosa and lung specimens, which authentically recapitulated the ACE2 expression pattern in human paranasal sinus specimens. Thus, ACE2 protein expression demonstrates a significant gradient between upper and lower respiratory tract in humans and is scarce in the lung. This pattern of ACE2 expression supports the notion of sinonasal epithelium being the main entry site for SARS-CoV-2 but raises further questions on the pathogenesis and cellular targets of SARS-CoV-2 in COVID-19 pneumonia.<\/jats:p>","DOI":"10.1371\/journal.pone.0247510","type":"journal-article","created":{"date-parts":[[2021,2,24]],"date-time":"2021-02-24T18:43:35Z","timestamp":1614192215000},"page":"e0247510","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":22,"title":["Comparative analysis of ACE2 protein expression in rodent, non-human primate, and human respiratory tract at baseline and after injury: A conundrum for COVID-19 pathogenesis"],"prefix":"10.1371","volume":"16","author":[{"given":"Sourabh","family":"Soni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohannes","family":"Tesfaigzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason L.","family":"Hornick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1459-3607","authenticated-orcid":true,"given":"Sule","family":"\u00c7ataltepe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,2,24]]},"reference":[{"issue":"2","key":"pone.0247510.ref001","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1006\/viro.2000.0757","article-title":"Coronavirus spike proteins in viral entry and pathogenesis","volume":"279","author":"TM Gallagher","year":"2001","journal-title":"Virology"},{"issue":"4","key":"pone.0247510.ref002","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1128\/JVI.02615-14","article-title":"Receptor recognition mechanisms of coronaviruses: a decade of structural studies","volume":"89","author":"F Li","year":"2015","journal-title":"J Virol"},{"issue":"6965","key":"pone.0247510.ref003","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/nature02145","article-title":"Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus","volume":"426","author":"W Li","year":"2003","journal-title":"Nature"},{"issue":"2","key":"pone.0247510.ref004","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"M Hoffmann","year":"2020","journal-title":"Cell"},{"issue":"7798","key":"pone.0247510.ref005","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41586-020-2012-7","article-title":"A pneumonia outbreak associated with a new coronavirus of probable bat origin","volume":"579","author":"P Zhou","year":"2020","journal-title":"Nature"},{"issue":"4","key":"pone.0247510.ref006","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/s41564-020-0688-y","article-title":"Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses","volume":"5","author":"M Letko","year":"2020","journal-title":"Nat Microbiol."},{"issue":"2","key":"pone.0247510.ref007","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.cell.2020.02.058","article-title":"Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein","volume":"181","author":"AC Walls","year":"2020","journal-title":"Cell"},{"issue":"5","key":"pone.0247510.ref008","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.devcel.2020.05.012","article-title":"Cigarette Smoke Exposure and Inflammatory Signaling Increase the Expression of the SARS-CoV-2 Receptor ACE2 in the Respiratory Tract","volume":"53","author":"JC Smith","year":"2020","journal-title":"Dev Cell"},{"issue":"12","key":"pone.0247510.ref009","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1164\/rccm.202003-0693LE","article-title":"Tobacco Smoking Increases the Lung Gene Expression of ACE2, the Receptor of SARS-CoV-2","volume":"201","author":"G Cai","year":"2020","journal-title":"Am J Respir Crit Care Med"},{"issue":"1","key":"pone.0247510.ref010","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1164\/rccm.202003-0821OC","article-title":"COVID-19-related Genes in Sputum Cells in Asthma. 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