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While it was known that SARS\u2010CoV\u20102 infects human hepatocytes, our study determines the mechanism of infection, demonstrates viral replication and spread, and highlights direct hepatocyte damage. Viral replication was readily detectable upon infection of primary human hepatocytes and hepatoma cells with the ancestral SARS\u2010CoV\u20102, Delta, and Omicron variants. Hepatocytes express the SARS\u2010CoV\u20102 receptor ACE2 and the host cell protease TMPRSS2, and knocking down ACE2 and TMPRSS2 impaired SARS\u2010CoV\u20102 infection. Progeny viruses released from infected hepatocytes showed the typical coronavirus morphology by electron microscopy and proved infectious when transferred to fresh cells, indicating that hepatocytes can contribute to virus spread. Importantly, SARS\u2010CoV\u20102 infection rapidly induced hepatocyte death in a replication\u2010dependent fashion, with the Omicron variant showing faster onset but less extensive cell death. C57BL\/6 wild\u2010type mice infected with a mouse\u2010adapted SARS\u2010CoV\u20102 strain showed high levels of viral RNA in liver and lung tissues. ALT peaked when viral RNA was cleared from the liver. Liver histology revealed profound tissue damage and immune cell infiltration, indicating that direct cytopathic effects of SARS\u2010CoV\u20102 and immune\u2010mediated killing of infected hepatocytes contribute to liver pathology.<\/jats:p>","DOI":"10.1002\/jmv.70156","type":"journal-article","created":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T12:35:10Z","timestamp":1736166910000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["SARS\u2010CoV\u20102 Productively Infects Human Hepatocytes and Induces Cell Death"],"prefix":"10.1002","volume":"97","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6512-1602","authenticated-orcid":false,"given":"Chunkyu","family":"Ko","sequence":"first","affiliation":[{"name":"Institute of Virology Technical University of Munich\/Helmholtz Munich Munich Germany"},{"name":"Infectious Diseases Therapeutic Research Center Korea Research Institute of Chemical Technology (KRICT) Daejeon South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cho\u2010Chin","family":"Cheng","sequence":"additional","affiliation":[{"name":"Institute of Virology Technical University of Munich\/Helmholtz Munich Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Mistretta","sequence":"additional","affiliation":[{"name":"Institute of Virology Technical University of Munich\/Helmholtz Munich Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shubhankar","family":"Ambike","sequence":"additional","affiliation":[{"name":"Institute of Virology Technical University of Munich\/Helmholtz Munich Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Sacherl","sequence":"additional","affiliation":[{"name":"Institute of Virology Technical University of Munich\/Helmholtz Munich Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stoyan","family":"Velkov","sequence":"additional","affiliation":[{"name":"Institute of Virology Technical University of Munich\/Helmholtz Munich Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo\u2010Hung","family":"Liao","sequence":"additional","affiliation":[{"name":"Institute of Virology Technical University of Munich\/Helmholtz Munich Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romina","family":"Bester","sequence":"additional","affiliation":[{"name":"Institute of Virology Technical University of Munich\/Helmholtz Munich Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merve","family":"G\u00fcltan","sequence":"additional","affiliation":[{"name":"Institute of Virology Technical University of Munich\/Helmholtz Munich Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Polezhaeva","sequence":"additional","affiliation":[{"name":"Institute of Virology Technical University of Munich\/Helmholtz Munich Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Herrmann","sequence":"additional","affiliation":[{"name":"Institute of Virology Technical University of Munich\/Helmholtz Munich Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constanze A.","family":"Jakwerth","sequence":"additional","affiliation":[{"name":"Center of Allergy &amp; 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