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Esser, K. ; Cheng, X. ; Wettengel, J.M. ; Lucifora, J.* ; Hansen-Palmus, L. ; Austen, K. ; Roca Suarez, A.A.* ; Heintz, S.* ; Testoni, B.* ; Nebioglu, F.* ; Pham, M.T.* ; Yang, S.* ; Zernecke, A.* ; Wohlleber, D.* ; Ringelhan, M.* ; Broxtermann, M. ; Hartmann, D.* ; Hüser, N.* ; Mergner, J.* ; Pichlmair, A. ; Thasler, W.E.* ; Heikenwälder, M. ; Gasteiger, G. ; Blutke, A. ; Walch, A.K. ; Knolle, P.A.* ; Bartenschlager, R.* ; Protzer, U.

Hepatitis B virus targets lipid transport pathways to infect hepatocytes.

Cell. Mol. Gast. Hept. 16, 201-221 (2023)
DOI PMC
Creative Commons Lizenzvertrag
Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.
BACKGROUND & AIMS: A single hepatitis B virus (HBV) particle is sufficient to establish chronic infection of the liver after intravenous injection, suggesting that the virus targets hepatocytes via a highly efficient transport pathway. We therefore investigated whether HBV uses a physiological liver-directed pathway that supports specific host-cell targeting in vivo. METHODS: We established the ex vivo perfusion of intact human liver tissue that recapitulates the liver physiology to investigate HBV liver targeting. This model allowed us to investigate virus-host cell interactions in a cellular microenvironment mimicking the in vivo situation. RESULTS: HBV was rapidly sequestered by liver macrophages within 1 hour after a virus pulse perfusion but was detected in hepatocytes only after 16 hours. We found that HBV associates with lipoproteins in serum and within machrophages. Electron and immunofluorescence microscopy corroborated a co-localization in recycling endosomes within peripheral and liver macrophages. Recycling endosomes accumulated HBV and cholesterol, followed by transport of HBV back to the cell surface along the cholesterol efflux pathway. To reach hepatocytes as final target cells, HBV was able to utilize the hepatocyte-directed cholesterol transport machinery of macrophages. CONCLUSIONS: Our results propose that by binding to liver targeted lipoproteins and using the reverse cholesterol transport pathway of macrophages, HBV hijacks the physiological lipid transport pathways to the liver to most efficiently reach its target organ. This may involve transinfection of liver macrophages and result in deposition of HBV in the perisinusoidal space from where HBV can bind its receptor on hepatocytes.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Lipoprotein Metabolism ; Liver Targeting ; Transcytosis ; Transinfection; Apolipoprotein-e; Sinusoidal Endothelium; Lipoprotein-lipase; Malaria Sporozoite; Apoprotein-e; Rat-liver; Dc-sign; Binding; Cells; Proteoglycans
ISSN (print) / ISBN 2352-345X
e-ISSN 2352-345X
Journal Cellular and Molecular Gastroenterology and Hepatology
Quellenangaben Volume: 16, Issue: 2, Pages: 201-221 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Non-patent literature Publications
Institute(s) Institute of Virology (VIRO)
Research Unit Analytical Pathology (AAP)
Grants French National Research Agency (ANR) as part of the second "Investissements d'Avenir" program
European Union
German Center for Infection Research (DZIF)
Deutsche Forschungsgemeinschaft