{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T14:00:57Z","timestamp":1791381657478,"version":"4.3.3"},"reference-count":39,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T00:00:00Z","timestamp":1777939200000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Medical Virology"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Mice are valuable small animal models for studying SARS\u2010CoV\u20102 pathogenesis. Ancestral SARS\u2010CoV\u20102 strains do not efficiently utilize murine\n                    <jats:italic>Ace2<\/jats:italic>\n                    , rendering wild\u2010type mice resistant to infection. Although human ACE2 transgenic models such as K18\u2010hACE2 have provided critical insights, they express multiple copies of both murine and human ACE2, and random transgene insertion can result in non\u2010physiological receptor expression. To overcome these limitations, we employed a human ACE2 knock\u2010in (hACE2\u2010KI) model in which the murine\n                    <jats:italic>Ace2<\/jats:italic>\n                    coding sequence is replaced with human ACE2 using CRISPR\/Cas9 technology, generating an mAce2\u2010null background. This design allows human ACE2 expression under endogenous regulatory control while eliminating murine\n                    <jats:italic>Ace2<\/jats:italic>\n                    expression, thereby providing a more physiologically relevant platform to investigate SARS\u2010CoV\u20102 pathogenesis and evaluate therapeutic and preventive strategies. In this study, SARS\u2010CoV\u20102\u2010associated disease was evaluated and compared among hACE2\u2010KI, K18\u2010hACE2 and C57BL\/6J mice. Mice were intranasally inoculated with 10\n                    <jats:sup>5<\/jats:sup>\n                    plaque\u2010forming units of SARS\u2010CoV\u20102 lineages B.1 or B.1.351. Both hACE2\u2010KI and K18\u2010hACE2 mice developed severe disease after SARS\u2010CoV\u20102 infection. Following infection with B.1, both K18\u2010hACE2 mice and hACE2\u2010KI mice exhibited significant weight loss and mortality, with high viral loads detected in the lungs and brain. hACE2\u2010KI mice infected with SARS\u2010CoV\u20102 B.1.351 also showed significant weight loss and viral loads, resulting in high mortality. The pathology and inflammatory response within the lungs and brain of infected hACE2\u2010KI mice revealed robust expression of viral nucleocapsid protein, histopathological changes, and upregulated cytokine and chemokine responses. Together, these findings demonstrate that the hACE2\u2010KI knock\u2010in mouse model supports robust SARS\u2010CoV\u20102 replication and mimics severe COVID\u201019 disease.\n                  <\/jats:p>","DOI":"10.1002\/jmv.70959","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T12:26:09Z","timestamp":1777983969000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Humanized Lethal Mouse Model of SARS\u2010CoV\u20102\u2010Associated Disease"],"prefix":"10.1002","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2314-3437","authenticated-orcid":false,"given":"Shannon","family":"Stone","sequence":"first","affiliation":[{"name":"Department of Biology College of Arts and Sciences, Georgia State University Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amany","family":"Elsharkawy","sequence":"additional","affiliation":[{"name":"Department of Biology College of Arts and Sciences, Georgia State University Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lila D.","family":"Patterson","sequence":"additional","affiliation":[{"name":"Department of Biology College of Arts and Sciences, Georgia State University Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janhavi P.","family":"Natekar","sequence":"additional","affiliation":[{"name":"Department of Biology College of Arts and Sciences, Georgia State University Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Envigo, an Inotiv Company GEMS R&amp;D Group St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Viktoria Hyddmark","sequence":"additional","affiliation":[{"name":"Envigo, an Inotiv Company GEMS R&amp;D Group St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeannie","family":"Camarillo","sequence":"additional","affiliation":[{"name":"Envigo, an Inotiv Company GEMS R&amp;D Group St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guojun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Envigo, an Inotiv Company GEMS R&amp;D Group St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0970-4875","authenticated-orcid":false,"given":"Mukesh","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Biology College of Arts and Sciences, Georgia State University Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,5]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-020-0688-y"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/v13010132"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens9070538"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2020.102433"},{"issue":"5","key":"e_1_2_11_6_1","article-title":"Neurological Complications of Coronavirus Disease (COVID\u201019): Encephalopathy, MRI Brain and Cerebrospinal Fluid Findings: Case 2","volume":"12","author":"Espinosa P. 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