Targeting Cholesterol Metabolism as Efficient Antiviral Strategy Against the Hepatitis E VirusSummary
| Autor: | Evelyn Seelow, Eberhard Hildt, Denna Tabari, Kathrin Woytinek, David Heiler Martín, Catharina Scholl, Julia C. Stingl, Mira Choi, Benjamin Schmidt, Mirco Glitscher |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
viruses Hepatitis E HEV Lysosomes Lipids Cholesterol Antiviral RC799-869 Pharmacology Virus Replication medicine.disease_cause DMEM Dulbecco’s modified Eagle’s medium chemistry.chemical_compound 0302 clinical medicine Fenofibrate Hepatitis E virus LDL low-density lipoprotein Tumor Cells Cultured 25-HC 25-hydroxycholesterol RT-qPCR reverse-transcription quantitative polymerase chain reaction Original Research medicine.diagnostic_test Gastroenterology virus diseases Diseases of the digestive system. Gastroenterology FGF19 fibroblast growth factor 19 MVB multivesicular body EC50 half maximal effective concentration qPCR quantitative polymerase chain reaction 030211 gastroenterology & hepatology lipids (amino acids peptides and proteins) Intracellular eHEV quasi-enveloped hepatitis E virus medicine.drug Cell Survival Endosome HDL high-density lipoprotein HEV hepatitis E virus LAMP2 lysosome-associated membrane protein 2 Cyclosporins TCID50 half maximal tissue culture infective dose Microbial Sensitivity Tests Antiviral Agents 03 medical and health sciences Western blot medicine Humans Centrifugation Hepatology business.industry digestive system diseases CI confidence interval 030104 developmental biology chemistry Simvastatin business PCSK9 proprotein convertase subtilisin/kexin type 9 |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 1, Pp 159-180 (2021) Cellular and Molecular Gastroenterology and Hepatology : CMGH 12, 159-180 (2021). doi:10.1016/j.jcmgh.2021.02.002 Cellular and Molecular Gastroenterology and Hepatology, 12(1):159-180 Cellular and Molecular Gastroenterology and Hepatology |
| DOI: | 10.1016/j.jcmgh.2021.02.002 |
| Popis: | Background and aims The Hepatitis E virus hijacks the endosomal system for its release. These structures are highly dependent on cholesterol. Hence, this study investigates the impact of HEV on cholesterol-metabolism, the effect of intracellular cholesterol content on HEV-release and the potential of cholesterol-modulators to serve as antivirals. Methods Intracellular cholesterol-content of cells was modulated and impacts on HEV were monitored using qPCR, Western blot, microscopy, virus-titration and density-gradient centrifugation. Blood-lipids and HEV-RNA were routinely quantified in chronically infected patients during follow-up visits. Results In HEV-infected cells, decreased levels of cholesterol are found. In patients, HEV infection decreases serum-lipid concentrations. Importantly, statin treatment herein increases viral titers. Similarly, reduction of intracellular cholesterol via simvastatin treatment increases viral release in vitro. On the contrary, elevating intracellular cholesterol via LDL or 25-hydroxycholesterol strongly reduces viral release due to enhanced lysosomal degradation of HEV. Drug-induced elevation of intracellular cholesterol via fenofibrate or PSC833 impairs HEV release via the same mechanism. Conclusions This study analyses the crosstalk between HEV and intracellular cholesterol. The results highlight the importance of an intact cholesterol homeostasis for HEV-release and thereby identify a potential target for antiviral strategies. Especially fenofibrate is considered a promising novel antiviral against HEV. Beyond this, the study may help clinicians evaluating co-treatments of HEV-infected patients with statins, as this may be counter indicated. Graphical abstract |
| Databáze: | OpenAIRE |
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