{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T16:55:50Z","timestamp":1792688150662,"version":"4.5.0"},"reference-count":69,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T00:00:00Z","timestamp":1646438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K22 AI144050"],"award-info":[{"award-number":["K22 AI144050"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21 ES032882"],"award-info":[{"award-number":["R21 ES032882"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10OD030269"],"award-info":[{"award-number":["S10OD030269"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10OD026983"],"award-info":[{"award-number":["S10OD026983"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1UL1TR001430"],"award-info":[{"award-number":["1UL1TR001430"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008294","name":"Louisiana State University","doi-asserted-by":"publisher","award":["PG002165"],"award-info":[{"award-number":["PG002165"]}],"id":[{"id":"10.13039\/100008294","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Animal models recapitulating COVID-19 are critical to enhance our understanding of SARS-CoV-2 pathogenesis. Intranasally inoculated transgenic mice expressing human angiotensin-converting enzyme 2 under the cytokeratin 18 promoter (K18-hACE2) represent a lethal model of SARS-CoV-2 infection. We evaluated the clinical and virological dynamics of SARS-CoV-2 using two intranasal doses (104 and 106 PFUs), with a detailed spatiotemporal pathologic analysis of the 106 dose cohort. Despite generally mild-to-moderate pneumonia, clinical decline resulting in euthanasia or death was commonly associated with hypothermia and viral neurodissemination independent of inoculation dose. Neuroinvasion was first observed at 4 days post-infection, initially restricted to the olfactory bulb suggesting axonal transport via the olfactory neuroepithelium as the earliest portal of entry. Absence of viremia suggests neuroinvasion occurs independently of transport across the blood-brain barrier. SARS-CoV-2 tropism was neither restricted to ACE2-expressing cells (e.g., AT1 pneumocytes), nor inclusive of some ACE2-positive cell lineages (e.g., bronchiolar epithelium and brain vasculature). Absence of detectable ACE2 protein expression in neurons but overexpression in neuroepithelium suggest this as the most likely portal of neuroinvasion, with subsequent ACE2 independent lethal neurodissemination. A paucity of epidemiological data and contradicting evidence for neuroinvasion and neurodissemination in humans call into question the translational relevance of this model.<\/jats:p>","DOI":"10.3390\/v14030535","type":"journal-article","created":{"date-parts":[[2022,3,6]],"date-time":"2022-03-06T20:40:38Z","timestamp":1646599238000},"page":"535","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":92,"title":["Fatal Neurodissemination and SARS-CoV-2 Tropism in K18-hACE2 Mice Is Only Partially Dependent on hACE2 Expression"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3864-5915","authenticated-orcid":false,"given":"Mariano","family":"Carossino","sequence":"first","affiliation":[{"name":"Louisiana Animal Disease Diagnostic Laboratory (LADDL), Louisiana State University, Baton Rouge, LA 61329, USA"},{"name":"Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 61329, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devin","family":"Kenney","sequence":"additional","affiliation":[{"name":"National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA 02118, USA"},{"name":"Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aoife K.","family":"O\u2019Connell","sequence":"additional","affiliation":[{"name":"National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paige","family":"Montanaro","sequence":"additional","affiliation":[{"name":"National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA 02118, USA"},{"name":"Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna E.","family":"Tseng","sequence":"additional","affiliation":[{"name":"National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA 02118, USA"},{"name":"Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans P.","family":"Gertje","sequence":"additional","affiliation":[{"name":"National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle A.","family":"Grosz","sequence":"additional","affiliation":[{"name":"National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4563-3683","authenticated-orcid":false,"given":"Maria","family":"Ericsson","sequence":"additional","affiliation":[{"name":"Electron Microscopy Core Facility, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertrand R.","family":"Huber","sequence":"additional","affiliation":[{"name":"Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna A.","family":"Kurnick","sequence":"additional","affiliation":[{"name":"National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0194-5044","authenticated-orcid":false,"given":"Saravanan","family":"Subramaniam","sequence":"additional","affiliation":[{"name":"Department of Medicine, Pulmonary Center, Boston University School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0859-5785","authenticated-orcid":false,"given":"Thomas A.","family":"Kirkland","sequence":"additional","affiliation":[{"name":"Promega Biosciences, LLC, San Luis Obispo, CA 93401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel R.","family":"Walker","sequence":"additional","affiliation":[{"name":"Promega Biosciences, LLC, San Luis Obispo, CA 93401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin P.","family":"Francis","sequence":"additional","affiliation":[{"name":"Perkin Elmer, Hopkinton, MA 01748, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander D.","family":"Klose","sequence":"additional","affiliation":[{"name":"InVivo Analytics Inc., New York, NY 10023, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neal","family":"Paragas","sequence":"additional","affiliation":[{"name":"InVivo Analytics Inc., New York, NY 10023, USA"},{"name":"Department of Radiology Imaging Research Lab, University of Washington, Seattle, WA 98133, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2773-1033","authenticated-orcid":false,"given":"Markus","family":"Bosmann","sequence":"additional","affiliation":[{"name":"National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA 02118, USA"},{"name":"Department of Medicine, Pulmonary Center, Boston University School of Medicine, Boston, MA 02118, USA"},{"name":"Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohsan","family":"Saeed","sequence":"additional","affiliation":[{"name":"National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA 02118, USA"},{"name":"Department of Biochemistry, Boston University, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0609-678X","authenticated-orcid":false,"given":"Udeni B. 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