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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)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Lipoprotein Metabolism ; Liver Targeting ; Transcytosis ; Transinfection; Apolipoprotein-e; Sinusoidal Endothelium; Lipoprotein-lipase; Malaria Sporozoite; Apoprotein-e; Rat-liver; Dc-sign; Binding; Cells; Proteoglycans
Sprache englisch
Veröffentlichungsjahr 2023
HGF-Berichtsjahr 2023
ISSN (print) / ISBN 2352-345X
e-ISSN 2352-345X
Zeitschrift Cellular and Molecular Gastroenterology and Hepatology
Quellenangaben Band: 16, Heft: 2, Seiten: 201-221 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort New York, NY
Institut(e) Institute of Virology (VIRO)
Research Unit Analytical Pathology (AAP)
POF Topic(s) 30203 - Molecular Targets and Therapies
30205 - Bioengineering and Digital Health
Forschungsfeld(er) Immune Response and Infection
Enabling and Novel Technologies
PSP-Element(e) G-502700-003
G-502700-001
G-500390-001
Förderungen French National Research Agency (ANR) as part of the second "Investissements d'Avenir" program
European Union
German Center for Infection Research (DZIF)
Deutsche Forschungsgemeinschaft
DOI 10.1016/j.jcmgh.2023.03.011
WOS ID 001028375000001
Scopus ID 85161973924
PubMed ID 37054914
Erfassungsdatum 2023-10-06
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