{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:45:04Z","timestamp":1792025104862,"version":"4.4.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1009195","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,2,10]],"date-time":"2021-02-10T00:00:00Z","timestamp":1612915200000}}],"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T00:00:00Z","timestamp":1611014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["1ZIAAI001179-01"],"award-info":[{"award-number":["1ZIAAI001179-01"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    SARS-CoV-2 emerged in late 2019 and resulted in the ongoing COVID-19 pandemic. Several animal models have been rapidly developed that recapitulate the asymptomatic to moderate disease spectrum. Now, there is a direct need for additional small animal models to study the pathogenesis of severe COVID-19 and for fast-tracked medical countermeasure development. Here, we show that transgenic mice expressing the human SARS-CoV-2 receptor (angiotensin-converting enzyme 2 [hACE2]) under a cytokeratin 18 promoter (K18) are susceptible to SARS-CoV-2 and that infection resulted in a dose-dependent lethal disease course. After inoculation with either 10\n                    <jats:sup>4<\/jats:sup>\n                    TCID\n                    <jats:sub>50<\/jats:sub>\n                    or 10\n                    <jats:sup>5<\/jats:sup>\n                    TCID\n                    <jats:sub>50<\/jats:sub>\n                    , the SARS-CoV-2 infection resulted in rapid weight loss in both groups and uniform lethality in the 10\n                    <jats:sup>5<\/jats:sup>\n                    TCID\n                    <jats:sub>50<\/jats:sub>\n                    group. High levels of viral RNA shedding were observed from the upper and lower respiratory tract and intermittent shedding was observed from the intestinal tract. Inoculation with SARS-CoV-2 resulted in upper and lower respiratory tract infection with high infectious virus titers in nasal turbinates, trachea and lungs. The observed interstitial pneumonia and pulmonary pathology, with SARS-CoV-2 replication evident in pneumocytes, were similar to that reported in severe cases of COVID-19. SARS-CoV-2 infection resulted in macrophage and lymphocyte infiltration in the lungs and upregulation of Th1 and proinflammatory cytokines\/chemokines. Extrapulmonary replication of SARS-CoV-2 was observed in the cerebral cortex and hippocampus of several animals at 7 DPI but not at 3 DPI. The rapid inflammatory response and observed pathology bears resemblance to COVID-19. Additionally, we demonstrate that a mild disease course can be simulated by low dose infection with 10\n                    <jats:sup>2<\/jats:sup>\n                    TCID\n                    <jats:sub>50<\/jats:sub>\n                    SARS-CoV-2, resulting in minimal clinical manifestation and near uniform survival. Taken together, these data support future application of this model to studies of pathogenesis and medical countermeasure development.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1009195","type":"journal-article","created":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T13:47:37Z","timestamp":1611064057000},"page":"e1009195","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":294,"title":["K18-hACE2 mice develop respiratory disease resembling severe COVID-19"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5195-5478","authenticated-orcid":true,"given":"Claude Kwe","family":"Yinda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0489-6591","authenticated-orcid":true,"given":"Julia R.","family":"Port","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trenton","family":"Bushmaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8523-955X","authenticated-orcid":true,"given":"Irene","family":"Offei Owusu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6190-4199","authenticated-orcid":true,"given":"Jyothi N.","family":"Purushotham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria A.","family":"Avanzato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1816-472X","authenticated-orcid":true,"given":"Robert J.","family":"Fischer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5462-5952","authenticated-orcid":true,"given":"Jonathan E.","family":"Schulz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6669-0583","authenticated-orcid":true,"given":"Myndi G.","family":"Holbrook","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4415-762X","authenticated-orcid":true,"given":"Madison J.","family":"Hebner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3779-7423","authenticated-orcid":true,"given":"Rebecca","family":"Rosenke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0186-9587","authenticated-orcid":true,"given":"Andrea","family":"Marzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0206-297X","authenticated-orcid":true,"given":"Sonja M.","family":"Best","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9763-7758","authenticated-orcid":true,"given":"Emmie","family":"de Wit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8907-8821","authenticated-orcid":true,"given":"Carl","family":"Shaia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4368-6359","authenticated-orcid":true,"given":"Neeltje","family":"van Doremalen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2288-3196","authenticated-orcid":true,"given":"Vincent J.","family":"Munster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,1,19]]},"reference":[{"key":"ppat.1009195.ref001","unstructured":"WHO. 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Angiotensin-Converting Enzyme 2","author":"RD Jiang","year":"2020","journal-title":"Cell"},{"key":"ppat.1009195.ref033","article-title":"Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling","author":"B Israelow","year":"2020","journal-title":"bioRxiv"},{"key":"ppat.1009195.ref034","article-title":"Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease","volume":"2020","author":"JW Golden","journal-title":"bioRxiv"},{"key":"ppat.1009195.ref035","article-title":"Evaluation of K18-hACE2 mice as a model of SARS-CoV-2 infection","volume":"2020","author":"GB Moreau","journal-title":"bioRxiv"},{"issue":"5","key":"ppat.1009195.ref036","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.jtho.2020.02.010","article-title":"Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer","volume":"15","author":"S Tian","journal-title":"J Thorac Oncol. 2020"},{"issue":"24","key":"ppat.1009195.ref037","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.1001\/jama.2020.8907","article-title":"Postmortem Examination of Patients With COVID-19","volume":"323","author":"T Schaller","year":"2020","journal-title":"JAMA"},{"key":"ppat.1009195.ref038","article-title":"Pulmonary and Cardiac Pathology in Covid-19: The First Autopsy Series from New Orleans","volume":"2020","author":"SE Fox","journal-title":"medRxiv"},{"issue":"6","key":"ppat.1009195.ref039","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1093\/nsr\/nwaa037","article-title":"Elevated plasma levels of selective cytokines in COVID-19 patients reflect viral load and lung injury","volume":"7","author":"Y Liu","journal-title":"National Science Review. 2020"},{"key":"ppat.1009195.ref040","article-title":"Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia 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