{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T11:03:04Z","timestamp":1775559784856,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pbio.3001989","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T00:00:00Z","timestamp":1676505600000}}],"reference-count":78,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T00:00:00Z","timestamp":1675641600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL39552-04S1"],"award-info":[{"award-number":["R01HL39552-04S1"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["963048"],"award-info":[{"award-number":["963048"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI109022"],"award-info":[{"award-number":["R01AI109022"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21AI156731"],"award-info":[{"award-number":["R21AI156731"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Health","award":["T32EB023860"],"award-info":[{"award-number":["T32EB023860"]}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R25GM125597"],"award-info":[{"award-number":["R25GM125597"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI138370"],"award-info":[{"award-number":["R01AI138370"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["906488"],"award-info":[{"award-number":["906488"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006920","name":"University of Pennsylvania","doi-asserted-by":"crossref","award":["Penn CVI Dream Team grant"],"award-info":[{"award-number":["Penn CVI Dream Team grant"]}],"id":[{"id":"10.13039\/100006920","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosbiology.org"],"crossmark-restriction":false},"short-container-title":["PLoS Biol"],"abstract":"<jats:p>Angiotensin-converting enzyme 2 (ACE2) is the cell-surface receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). While its central role in Coronavirus Disease 2019 (COVID-19) pathogenesis is indisputable, there remains significant debate regarding the role of this transmembrane carboxypeptidase in the disease course. These include the role of soluble versus membrane-bound ACE2, as well as ACE2-independent mechanisms that may contribute to viral spread. Testing these roles requires in vivo models. Here, we report humanized ACE2-floxed mice in which hACE2 is expressed from the mouse <jats:italic>Ace2<\/jats:italic> locus in a manner that confers lethal disease and permits cell-specific, Cre-mediated loss of function, and LSL-hACE2 mice in which hACE2 is expressed from the <jats:italic>Rosa26<\/jats:italic> locus enabling cell-specific, Cre-mediated gain of function. Following exposure to SARS-CoV-2, hACE2-floxed mice experienced lethal cachexia, pulmonary infiltrates, intravascular thrombosis and hypoxemia\u2014hallmarks of severe COVID-19. Cre-mediated loss and gain of hACE2 demonstrate that neuronal infection confers lethal cachexia, hypoxemia, and respiratory failure in the absence of lung epithelial infection. In this series of genetic experiments, we demonstrate that ACE2 is absolutely and cell-autonomously required for SARS-CoV-2 infection in the olfactory epithelium, brain, and lung across diverse cell types. Therapies inhibiting or blocking ACE2 at these different sites are likely to be an effective strategy towards preventing severe COVID-19.<\/jats:p>","DOI":"10.1371\/journal.pbio.3001989","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T18:43:31Z","timestamp":1675709011000},"page":"e3001989","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Cell-autonomous requirement for ACE2 across organs in lethal mouse SARS-CoV-2 infection"],"prefix":"10.1371","volume":"21","author":[{"given":"Alan T.","family":"Tang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David W.","family":"Buchholz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine M.","family":"Szigety","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Imbiakha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siqi","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maxwell","family":"Frankfurter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jisheng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Hewins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Mericko-Ishizuka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N Adrian","family":"Leu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Sterling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isaac A.","family":"Monreal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"Sahler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Avery","family":"August","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuming","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kellie A.","family":"Jurado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward E.","family":"Morrisey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah E.","family":"Millar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hector C.","family":"Aguilar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6489-7086","authenticated-orcid":true,"given":"Mark L.","family":"Kahn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,2,6]]},"reference":[{"issue":"7798","key":"pbio.3001989.ref001","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":"2","key":"pbio.3001989.ref002","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":"6485","key":"pbio.3001989.ref003","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1126\/science.abb2762","article-title":"Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2","volume":"367","author":"R Yan","year":"2020","journal-title":"Science"},{"issue":"7843","key":"pbio.3001989.ref004","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/s41586-020-2943-z","article-title":"COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice","volume":"589","author":"J Zheng","year":"2021","journal-title":"Nature"},{"issue":"6","key":"pbio.3001989.ref005","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.tips.2004.04.001","article-title":"ACE2: from vasopeptidase to SARS virus receptor","volume":"25","author":"AJ Turner","year":"2004","journal-title":"Trends Pharmacol Sci"},{"issue":"34","key":"pbio.3001989.ref006","doi-asserted-by":"crossref","first-page":"30113","DOI":"10.1074\/jbc.M505111200","article-title":"Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2)","volume":"280","author":"DW Lambert","year":"2005","journal-title":"J Biol Chem"},{"issue":"7865","key":"pbio.3001989.ref007","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/s41586-021-03570-8","article-title":"COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets","volume":"595","author":"TM Delorey","year":"2021","journal-title":"Nature"},{"issue":"8","key":"pbio.3001989.ref008","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1016\/j.cell.2021.02.053","article-title":"Soluble ACE2-mediated cell entry of SARS-CoV-2 via interaction with proteins related to the renin-angiotensin system","volume":"184","author":"ML Yeung","year":"2021","journal-title":"Cell"},{"issue":"4","key":"pbio.3001989.ref009","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.cell.2020.04.004","article-title":"Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2","volume":"181","author":"V Monteil","year":"2020","journal-title":"Cell"},{"issue":"11","key":"pbio.3001989.ref010","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1016\/S2213-2600(20)30418-5","article-title":"Human recombinant soluble ACE2 in severe COVID-19","volume":"8","author":"A Zoufaly","year":"2020","journal-title":"Lancet Respir Med"},{"issue":"1","key":"pbio.3001989.ref011","doi-asserted-by":"crossref","first-page":"e13426","DOI":"10.15252\/emmm.202013426","article-title":"Human soluble ACE2 improves the effect of remdesivir in SARS-CoV-2 infection","volume":"13","author":"V Monteil","year":"2021","journal-title":"EMBO Mol Med"},{"issue":"4","key":"pbio.3001989.ref012","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1681\/ASN.2020101537","article-title":"A Novel Soluble ACE2 Variant with Prolonged Duration of Action Neutralizes SARS-CoV-2 Infection in Human Kidney Organoids","volume":"32","author":"J Wysocki","year":"2021","journal-title":"J Am Soc Nephrol"},{"issue":"7","key":"pbio.3001989.ref013","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1681\/ASN.2021091209","article-title":"A Novel Soluble ACE2 Protein Provides Lung and Kidney Protection in Mice Susceptible to Lethal SARS-CoV-2 Infection","volume":"33","author":"L Hassler","year":"2022","journal-title":"J Am Soc Nephrol"},{"issue":"6518","key":"pbio.3001989.ref014","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1126\/science.abd3072","article-title":"Neuropilin-1 is a host factor for SARS-CoV-2 infection","volume":"370","author":"JL Daly","year":"2020","journal-title":"Science"},{"issue":"6","key":"pbio.3001989.ref015","doi-asserted-by":"crossref","first-page":"e2113874119","DOI":"10.1073\/pnas.2113874119","article-title":"Extracellular vimentin is an attachment factor that facilitates SARS-CoV-2 entry into human endothelial cells","volume":"119","author":"R Amraei","year":"2022","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pbio.3001989.ref016","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41580-021-00418-x","article-title":"Mechanisms of SARS-CoV-2 entry into cells","volume":"23","author":"CB Jackson","year":"2022","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"3","key":"pbio.3001989.ref017","doi-asserted-by":"crossref","first-page":"101710","DOI":"10.1016\/j.jbc.2022.101710","article-title":"Integrin mediates cell entry of the SARS-CoV-2 virus independent of cellular receptor ACE2","volume":"298","author":"J Liu","year":"2022","journal-title":"J Biol Chem"},{"issue":"1","key":"pbio.3001989.ref018","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2111400119","article-title":"SARS-CoV-2 spreads through cell-to-cell transmission","volume":"119","author":"C Zeng","year":"2022","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pbio.3001989.ref019","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.cell.2020.05.027","article-title":"Pathogenesis of SARS-CoV-2 in Transgenic Mice Expressing Human Angiotensin-Converting Enzyme 2","volume":"182","author":"RD Jiang","year":"2020","journal-title":"Cell"},{"issue":"7830","key":"pbio.3001989.ref020","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/s41586-020-2787-6","article-title":"Animal models for COVID-19","volume":"586","author":"C Munoz-Fontela","year":"2020","journal-title":"Nature"},{"issue":"1","key":"pbio.3001989.ref021","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.chom.2020.05.020","article-title":"A Mouse Model of SARS-CoV-2 Infection and Pathogenesis","volume":"28","author":"SH Sun","year":"2020","journal-title":"Cell Host Microbe"},{"issue":"12","key":"pbio.3001989.ref022","doi-asserted-by":"crossref","DOI":"10.1084\/jem.20201241","article-title":"Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling","volume":"217","author":"B Israelow","year":"2020","journal-title":"J Exp Med"},{"issue":"2","key":"pbio.3001989.ref023","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1128\/JVI.02012-06","article-title":"Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus","volume":"81","author":"PB McCray","year":"2007","journal-title":"J Virol"},{"issue":"7818","key":"pbio.3001989.ref024","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1038\/s41586-020-2312-y","article-title":"The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice","volume":"583","author":"L Bao","year":"2020","journal-title":"Nature"},{"issue":"7852","key":"pbio.3001989.ref025","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/s41586-021-03361-1","article-title":"SARS-CoV-2 spike D614G change enhances replication and transmission","volume":"592","author":"B Zhou","year":"2021","journal-title":"Nature"},{"issue":"1","key":"pbio.3001989.ref026","first-page":"R373","article-title":"Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system","volume":"292","author":"MF Doobay","year":"2007","journal-title":"Am J Phys Regul Integr Comp Phys"},{"issue":"12","key":"pbio.3001989.ref027","doi-asserted-by":"crossref","first-page":"101839","DOI":"10.1016\/j.isci.2020.101839","article-title":"SARS-CoV-2 Receptors and Entry Genes Are Expressed in the Human Olfactory Neuroepithelium and Brain","volume":"23","author":"L Fodoulian","year":"2020","journal-title":"iScience"},{"issue":"13","key":"pbio.3001989.ref028","article-title":"Nasal ciliated cells are primary targets for SARS-CoV-2 replication in the early stage of COVID-19","volume":"131","author":"JH Ahn","year":"2021","journal-title":"J Clin Invest"},{"issue":"1","key":"pbio.3001989.ref029","doi-asserted-by":"crossref","first-page":"5453","DOI":"10.1038\/s41467-020-19145-6","article-title":"ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs","volume":"11","author":"IT Lee","year":"2020","journal-title":"Nat Commun"},{"issue":"2","key":"pbio.3001989.ref030","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.cell.2020.05.042","article-title":"SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract","volume":"182","author":"YJ Hou","year":"2020","journal-title":"Cell"},{"key":"pbio.3001989.ref031","doi-asserted-by":"crossref","first-page":"102976","DOI":"10.1016\/j.ebiom.2020.102976","article-title":"Heterogeneous expression of the SARS-Coronavirus-2 receptor ACE2 in the human respiratory tract","volume":"60","author":"ME Ortiz","year":"2020","journal-title":"EBioMedicine"},{"issue":"5","key":"pbio.3001989.ref032","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.cell.2020.04.035","article-title":"SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues","volume":"181","author":"CGK Ziegler","year":"2020","journal-title":"Cell"},{"issue":"10229","key":"pbio.3001989.ref033","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/S0140-6736(20)30566-3","article-title":"Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study","volume":"395","author":"F Zhou","year":"2020","journal-title":"Lancet"},{"issue":"25","key":"pbio.3001989.ref034","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1056\/NEJMcp2009575","article-title":"Severe Covid-19","volume":"383","author":"DA Berlin","year":"2020","journal-title":"N Engl J Med"},{"issue":"7818","key":"pbio.3001989.ref035","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/s41586-020-2342-5","article-title":"Pathogenesis and transmission of SARS-CoV-2 in golden hamsters","volume":"583","author":"SF Sia","year":"2020","journal-title":"Nature"},{"key":"pbio.3001989.ref036","first-page":"JVI0151121","article-title":"SARS-CoV-2 causes lung infection without severe disease in human ACE2 knock-in mice","author":"ES Winkler","year":"2021","journal-title":"J Virol"},{"issue":"7837","key":"pbio.3001989.ref037","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/s41586-020-2700-3","article-title":"Sex differences in immune responses that underlie COVID-19 disease outcomes","volume":"588","author":"T Takahashi","year":"2020","journal-title":"Nature"},{"issue":"1","key":"pbio.3001989.ref038","doi-asserted-by":"crossref","first-page":"6317","DOI":"10.1038\/s41467-020-19741-6","article-title":"Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission","volume":"11","author":"H Peckham","year":"2020","journal-title":"Nat Commun"},{"issue":"10323","key":"pbio.3001989.ref039","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/S0140-6736(22)00017-4","article-title":"Early assessment of the clinical severity of the SARS-CoV-2 omicron variant in South Africa: a data linkage study","volume":"399","author":"N Wolter","year":"2022","journal-title":"Lancet"},{"issue":"5","key":"pbio.3001989.ref040","doi-asserted-by":"crossref","first-page":"177","DOI":"10.15585\/mmwr.mm7105e1","article-title":"SARS-CoV-2 Infection and Hospitalization Among Adults Aged >\/ = 18 Years, by Vaccination Status, Before and During SARS-CoV-2 B.1.1.529 (Omicron) Variant Predominance\u2014Los Angeles County, California, November 7, 2021-January 8, 2022.","volume":"71","author":"P Danza","year":"2022","journal-title":"MMWR Morb Mortal Wkly Rep"},{"issue":"7902","key":"pbio.3001989.ref041","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/s41586-022-04441-6","article-title":"SARS-CoV-2 Omicron virus causes attenuated disease in mice and hamsters","volume":"603","author":"PJ Halfmann","year":"2022","journal-title":"Nature"},{"issue":"7839","key":"pbio.3001989.ref042","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1038\/s41586-020-3014-1","article-title":"Progenitor identification and SARS-CoV-2 infection in human distal lung organoids","volume":"588","author":"AA Salahudeen","year":"2020","journal-title":"Nature"},{"key":"pbio.3001989.ref043","doi-asserted-by":"crossref","first-page":"6727","DOI":"10.1038\/ncomms7727","article-title":"Plasticity of Hopx(+) type I alveolar cells to regenerate type II cells in the lung","volume":"6","author":"R Jain","year":"2015","journal-title":"Nat Commun"},{"issue":"10","key":"pbio.3001989.ref044","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1016\/j.stem.2021.04.026","article-title":"Age-dependent alveolar epithelial plasticity orchestrates lung homeostasis and regeneration","volume":"28","author":"IJ Penkala","year":"2021","journal-title":"Cell Stem Cell"},{"issue":"4","key":"pbio.3001989.ref045","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.cell.2004.07.024","article-title":"Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities","volume":"118","author":"BD Harfe","year":"2004","journal-title":"Cell"},{"issue":"7860","key":"pbio.3001989.ref046","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/s41586-021-03475-6","article-title":"The spatial landscape of lung pathology during COVID-19 progression","volume":"593","author":"AF Rendeiro","year":"2021","journal-title":"Nature"},{"issue":"7865","key":"pbio.3001989.ref047","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/s41586-021-03569-1","article-title":"A molecular single-cell lung atlas of lethal COVID-19","volume":"595","author":"JC Melms","year":"2021","journal-title":"Nature"},{"issue":"2","key":"pbio.3001989.ref048","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1056\/NEJMoa2015432","article-title":"Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19","volume":"383","author":"M Ackermann","year":"2020","journal-title":"N Engl J Med"},{"issue":"5","key":"pbio.3001989.ref049","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/S2213-2600(20)30079-5","article-title":"Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study","volume":"8","author":"X Yang","year":"2020","journal-title":"Lancet Respir Med"},{"issue":"4","key":"pbio.3001989.ref050","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1183\/09031936.04.00096003","article-title":"The use of alveolar epithelial type I cell-selective markers to investigate lung injury and repair","volume":"24","author":"MC McElroy","year":"2004","journal-title":"Eur Respir J"},{"issue":"7","key":"pbio.3001989.ref051","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1016\/j.immuni.2021.06.002","article-title":"Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactions","volume":"54","author":"M Schwabenland","year":"2021","journal-title":"Immunity"},{"issue":"7868","key":"pbio.3001989.ref052","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/s41586-021-03710-0","article-title":"Dysregulation of brain and choroid plexus cell types in severe COVID-19","volume":"595","author":"AC Yang","year":"2021","journal-title":"Nature"},{"issue":"596","key":"pbio.3001989.ref053","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.abf8396","article-title":"COVID-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters","volume":"13","author":"GD de Melo","year":"2021","journal-title":"Sci Transl Med"},{"issue":"4","key":"pbio.3001989.ref054","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1177\/019262339502300404","article-title":"Olfactory toxicity of methimazole: dose-response and structure-activity studies and characterization of flavin-containing monooxygenase activity in the Long-Evans rat olfactory mucosa","volume":"23","author":"MB Genter","year":"1995","journal-title":"Toxicol Pathol"},{"issue":"1","key":"pbio.3001989.ref055","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.ydbio.2016.02.011","article-title":"Generation and analysis of an improved Foxg1-IRES-Cre driver mouse line","volume":"412","author":"D Kawaguchi","year":"2016","journal-title":"Dev Biol"},{"issue":"7","key":"pbio.3001989.ref056","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1002\/dvg.22866","article-title":"Generation of BAF53b-Cre transgenic mice with pan-neuronal Cre activities","volume":"53","author":"X Zhan","year":"2015","journal-title":"Genesis"},{"issue":"67","key":"pbio.3001989.ref057","doi-asserted-by":"crossref","first-page":"eabl9929","DOI":"10.1126\/sciimmunol.abl9929","article-title":"Administration of aerosolized SARS-CoV-2 to K18-hACE2 mice uncouples respiratory infection from fatal neuroinvasion","volume":"7","author":"V Fumagalli","year":"2022","journal-title":"Sci Immunol"},{"issue":"7941","key":"pbio.3001989.ref058","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/s41586-022-05542-y","article-title":"SARS-CoV-2 infection and persistence in the human body and brain at autopsy","volume":"612","author":"SR Stein","year":"2022","journal-title":"Nature"},{"issue":"11","key":"pbio.3001989.ref059","doi-asserted-by":"crossref","first-page":"e1002358","DOI":"10.1371\/journal.pgen.1002358","article-title":"A novel protein LZTFL1 regulates ciliary trafficking of the BBSome and Smoothened","volume":"7","author":"S Seo","year":"2011","journal-title":"PLoS Genet"},{"issue":"5","key":"pbio.3001989.ref060","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1136\/jmedgenet-2012-100737","article-title":"Exome sequencing identifies mutations in LZTFL1, a BBSome and smoothened trafficking regulator, in a family with Bardet\u2014Biedl syndrome with situs inversus and insertional polydactyly","volume":"49","author":"V Marion","year":"2012","journal-title":"J Med Genet"},{"issue":"4","key":"pbio.3001989.ref061","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1007\/s00726-014-1889-6","article-title":"Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors","volume":"47","author":"RN Vuille-dit-Bille","year":"2015","journal-title":"Amino Acids"},{"issue":"16","key":"pbio.3001989.ref062","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1056\/NEJMoa2020283","article-title":"Genomewide Association Study of Severe Covid-19 with Respiratory Failure","volume":"383","author":"GG Severe Covid","year":"2020","journal-title":"N Engl J Med"},{"issue":"7889","key":"pbio.3001989.ref063","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1038\/s41586-021-03767-x","article-title":"Mapping the human genetic architecture of COVID-19","volume":"600","author":"C-HG Initiative","year":"2021","journal-title":"Nature"},{"issue":"22","key":"pbio.3001989.ref064","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1001\/jama.2020.6825","article-title":"Management of COVID-19 Respiratory Distress","volume":"323","author":"JJ Marini","year":"2020","journal-title":"JAMA"},{"issue":"2","key":"pbio.3001989.ref065","doi-asserted-by":"crossref","first-page":"54","DOI":"10.5694\/mja2.50674","article-title":"COVID-19 acute respiratory distress syndrome (ARDS): clinical features and differences from typical pre-COVID-19 ARDS","volume":"213","author":"PG Gibson","year":"2020","journal-title":"Med J Aust"},{"key":"pbio.3001989.ref066","doi-asserted-by":"crossref","first-page":"154021","DOI":"10.1016\/j.jcrc.2022.154021","article-title":"Clinical characteristics, respiratory management, and determinants of oxygenation in COVID-19 ARDS: A prospective cohort study","volume":"71","author":"E Estenssoro","year":"2022","journal-title":"J Crit Care"},{"issue":"2","key":"pbio.3001989.ref067","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/s41593-020-00758-5","article-title":"Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19","volume":"24","author":"J Meinhardt","year":"2021","journal-title":"Nat Neurosci"},{"issue":"12","key":"pbio.3001989.ref068","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1001\/jamaneurol.2021.3821","article-title":"Anti-SARS-CoV-2 and Autoantibody Profiles in the Cerebrospinal Fluid of 3 Teenaged Patients With COVID-19 and Subacute Neuropsychiatric Symptoms","volume":"78","author":"CM Bartley","year":"2021","journal-title":"JAMA Neurol"},{"key":"pbio.3001989.ref069","article-title":"Brain imaging before and after COVID-19 in UK Biobank","author":"G Douaud","year":"2021","journal-title":"medRxiv"},{"key":"pbio.3001989.ref070","article-title":"SARS-CoV-2 infection and persistence throughout the human body and brain","author":"D Chertow","year":"2021","journal-title":"ResearchSquare"},{"issue":"11","key":"pbio.3001989.ref071","doi-asserted-by":"crossref","first-page":"e3001845","DOI":"10.1371\/journal.pbio.3001845","article-title":"SARS-CoV-2 infects human brain organoids causing cell death and loss of synapses that can be rescued by treatment with Sofosbuvir","volume":"20","author":"P Mesci","year":"2022","journal-title":"PLoS Biol"},{"issue":"24","key":"pbio.3001989.ref072","doi-asserted-by":"crossref","first-page":"5932","DOI":"10.1016\/j.cell.2021.10.027","article-title":"Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb","volume":"184","author":"M Khan","year":"2021","journal-title":"Cell"},{"issue":"6523","key":"pbio.3001989.ref073","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1126\/science.abe8499","article-title":"SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo","volume":"370","author":"YJ Hou","year":"2020","journal-title":"Science"},{"issue":"7908","key":"pbio.3001989.ref074","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1038\/s41586-022-04630-3","article-title":"Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19","volume":"605","author":"LR Wong","year":"2022","journal-title":"Nature"},{"issue":"4","key":"pbio.3001989.ref075","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1016\/j.cell.2020.09.050","article-title":"A Mouse-Adapted SARS-CoV-2 Induces Acute Lung Injury and Mortality in Standard Laboratory Mice","volume":"183","author":"SR Leist","year":"2020","journal-title":"Cell"},{"issue":"10","key":"pbio.3001989.ref076","doi-asserted-by":"crossref","first-page":"e20200140","DOI":"10.1084\/jem.20200140","article-title":"Cerebral cavernous malformations are driven by ADAMTS5 proteolysis of versican","volume":"217","author":"CC Hong","year":"2020","journal-title":"J Exp Med"},{"issue":"Suppl 1","key":"pbio.3001989.ref077","doi-asserted-by":"crossref","first-page":"S97","DOI":"10.1016\/S0925-4773(03)00099-6","article-title":"Efficient gene modulation in mouse epiblast using a Sox2Cre transgenic mouse strain","volume":"119","author":"S Hayashi","year":"2002","journal-title":"Mech Dev"},{"issue":"1","key":"pbio.3001989.ref078","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nn.2467","article-title":"A robust and high-throughput Cre reporting and characterization system for the whole mouse brain","volume":"13","author":"L Madisen","year":"2010","journal-title":"Nat Neurosci"}],"updated-by":[{"DOI":"10.1371\/journal.pbio.3001989","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T00:00:00Z","timestamp":1676505600000}}],"container-title":["PLOS Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3001989","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T18:50:01Z","timestamp":1676573401000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3001989"}},"subtitle":[],"editor":[{"given":"Frank","family":"Kirchhoff","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,2,6]]},"references-count":78,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2,6]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pbio.3001989","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pbio.3001989","asserted-by":"object"}]},"ISSN":["1545-7885"],"issn-type":[{"value":"1545-7885","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,6]]}}}