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Ko, C. ; Cheng, C.-C. ; Mistretta, D. ; Ambike, S. ; Sacherl, J. ; Velkov, S. ; Liao, B.-H. ; Bester, R. ; Gültan, M. ; Polezhaeva, O. ; Herrmann, A. ; Jakwerth, C.A. ; Schmidt-Weber, C.B. ; Bugert, J.J.* ; Wölfel, R.* ; Grass, V. ; Essbauer, S.* ; Schnepf, D.* ; Keppler, O.T.* ; Vondran, F.W.R.* ; Pichlmair, A. ; Mogler, C.* ; Ebert, G. ; Protzer, U.

SARS-CoV-2 productively infects human hepatocytes and induces cell death.

J. Med. Virol. 97:e70156 (2025)
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SARS-CoV-2 infection is accompanied by elevated liver enzymes, and patients with pre-existing liver conditions experience more severe disease. While it was known that SARS-CoV-2 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-CoV-2, Delta, and Omicron variants. Hepatocytes express the SARS-CoV-2 receptor ACE2 and the host cell protease TMPRSS2, and knocking down ACE2 and TMPRSS2 impaired SARS-CoV-2 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-CoV-2 infection rapidly induced hepatocyte death in a replication-dependent fashion, with the Omicron variant showing faster onset but less extensive cell death. C57BL/6 wild-type mice infected with a mouse-adapted SARS-CoV-2 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-CoV-2 and immune-mediated killing of infected hepatocytes contribute to liver pathology.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Ace2 ; Covid‐19 ; Sars‐cov‐2 ; Tmprss2 ; Hepatocytes ; Liver ; Tropism; Respiratory Syndrome Coronavirus; Angiotensin-converting Enzyme-2; Functional Receptor; Tmprss2; Ace2
Language english
Publication Year 2025
HGF-reported in Year 2025
ISSN (print) / ISBN 0146-6615
e-ISSN 1096-9071
Journal Journal of Medical Virology
Quellenangaben Volume: 97, Issue: 1, Pages: , Article Number: e70156 Supplement: ,
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)
Institute for Allergy Research (IAF)
POF-Topic(s) 30203 - Molecular Targets and Therapies
30202 - Environmental Health
Research field(s) Immune Response and Infection
Allergy
PSP Element(s) G-502700-003
G-502700-006
G-505400-001
G-502700-010
G-502799-701
Grants This study was supported by the German Research Foundation (DFG) via SFB-TRR179 (project 272983813 to U.P.), TRR22 (project 398577603 to C.S.W.) and TRR353 (project 471011418 to G.E.), by the State of Bavaria via research network FOR-COVID and Bay-VOC, by
DOI 10.1002/jmv.70156
WOS ID 001389938200001
Scopus ID 85214449569
PubMed ID 39760326
Erfassungsdatum 2025-03-19
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