1. Targeting Cholesterol Metabolism as Efficient Antiviral Strategy Against the Hepatitis E VirusSummary
- Author
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Evelyn Seelow, Eberhard Hildt, Denna Tabari, Kathrin Woytinek, David Heiler Martín, Catharina Scholl, Julia C. Stingl, Mira Choi, Benjamin Schmidt, and Mirco Glitscher
- Subjects
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 - Abstract
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
- Published
- 2021
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