Targeting cholesterol metabolism as efficient antiviral strategy against the Hepatitis E virus
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE157820 | GEO | 2021/02/12
REPOSITORIES: GEO
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Project description:Targeting cholesterol metabolism as efficient antiviral strategy against the Hepatitis E virus
| PRJNA662916 | ENA
Project description:Background and aimsThe 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.MethodsIntracellular 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.ResultsIn 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.ConclusionsThis 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.
| S-EPMC8099564 | biostudies-literature
Project description:Hepatitis E virus (HEV) is an important causative pathogen of acute hepatitis. Because of the absence of an in vitro culture system for HEV, research has been greatly impeded. And interaction between HEV and host cells was mainly studied by tansfection/transinfection system, such as Adeno virus transinfection system. We developed an in vitro culture system for HEV in PLC/PRF/5 cells. With this in vitro culture system, we studied the gene expression profile change by HEV infection. Using a microarray assay, we analysed genes of PLC/PRF/5 cells, whose transcription level could be changed by HEV infection.
2014-01-01 | GSE53731 | GEO
Project description:Hepatitis E virus (HEV) is an important causative pathogen of acute hepatitis. Because of the absence of an in vitro culture system for HEV, research has been greatly impeded. And interaction between HEV and host cells was mainly studied by tansfection/transinfection system, such as Adeno virus transinfection system. We developed an in vitro culture system for HEV in PLC/PRF/5 cells. With this in vitro culture system, we studied the gene expression profile change by HEV infection. Using a microarray assay, we analysed genes of PLC/PRF/5 cells, whose transcription level could be changed by HEV infection. Five flasks of PLC/PRF/5 cells inoculated with HEV were used as test sample, and five flasks inoculated with serum-free DMEM/199 medium were used as control samples. Both test and control flasks were cultured under the same conditions. Sixty days after inoculation, the test and control flasks was resolved with Trizol and analysed with Affymetrix HG-U133 Plus 2 array.
2014-01-01 | E-GEOD-53731 | biostudies-arrayexpress
Project description:Background: Human hepatitis E virus (HEV) usually causes a self-limiting disease, but especially immunocompromised individuals are at risk to develop a chronic and severe course of infection. Janus kinase (JAK) inhibitors (JAKi) are a novel drug class for the treatment of autoimmune inflammatory rheumatic disease (AIRD). As JAKs play a key role in innate immunity, viral infections and reactivations are frequently reported during JAKi treatment in AIRD patients. The aim of this study was to characterize the influence of JAKis on HEV replication in vivo and in authentic cell culture models ex vivo. Methods: We evaluated liver enzymes of an AIRD patient under JAKi therapy with hepatitis E and HEV infections in a cohort of AIRD patients. Experiments with HEV were performed by infection of primary human hepatocytes (PHHs) followed by immunofluorescence staining of viral markers and transcriptomic analysis. Results: Acute hepatitis was observed in a patient with AIRD and concomitant HEV infection. No acute infection could be detected in the AIRD cohort. Infection experiments in PHHs displayed an up to 50-fold increase of progeny virus production during JAKi treatment and transcriptomic analysis revealed induction of antiviral programs during infection. This induction was perturbed in the presence of JAKis, concomitant with elevated HEV RNA levels. Conclusion: Therapeutic JAK inhibition increases HEV replication by modulating the HEV-triggered immune response. Therefore, clinical monitoring of HEV infection during JAKi treatment and in case of elevated liver enzymes should be considered.
2023-02-09 | GSE224795 | GEO
Project description:Background: Hepatitis E Virus (HEV) is a new causative agent of chronic hepatitis in solid organ transplant recipients in Europe. Factors associated with the occurrence and persistence of chronic HEV infection remain largely unknown but chronic evolution seems to be the consequence of hostM-bM-^@M-^Ys immunological factors rather than of viral factors. Method: In a prospective case-control study, we have determined in whole blood of chronically HEV-infected kidney-transplant recipients the host response using microarray technology. Results: Chronically HEV-infected kidney-transplant recipients exhibited a specific transcriptional program, in which interferon effectors were prominent. The intensity of expression of each signatureM-bM-^@M-^Ys gene was significantly lower in patients who were subsequently cleared of HEV than in patients who were not. Furthermore, in patients who were cleared of HEV, a higher expression of these genes was associated with a longer delay until HEV clearance. Conclusions: The specific transcriptional program determined in chronically HEV-infected kidney-transplant recipients suggests an activation of type I interferon response. Intensity of interferon-stimulated genes expression could be useful to forecast the outcome of infection. High expression of interferon-stimulated genes could signify a dysregulation in the interferon response that might favour the persistence of the HEV infection. TrialM-bM-^@M-^Ys registration number: NCT01090232; RegistryM-bM-^@M-^Ys URL: http://clinicaltrials.gov/ct2/show/study/NCT01090232?term=kidney+transplant+recipients&cntry1=EU%3AFR&rank=2 Total RNA was extracted from whole-blood sample or monocytes of kidney-transplant patients with or without chronic hepatitis E (CHE) infection. Control patients were matched up with CHE patients for age, sex, time since kidney transplant and immunosuppressive treatment.
2013-01-29 | E-GEOD-36539 | biostudies-arrayexpress
Project description:The hepatitis E virus (HEV), a non enveloped RNA virus, causes viral hepatitis. The viral open reading frame 2 (ORF2) protein represents the capsid protein of HEV which is known to cause endoplasmic reticulum stress in ORF2 expressing cells. The initiation of endoplasmic reticulum stress induced apoptosis mainly involves the transcriptional activation of pro-apoptotic gene CHOP which will further trigger the major apoptotic pathways. However, the activation of CHOP by ORF2 protein in this study does not induce apoptotic markers such as Bax translocation to mitochondria. We have used the Affymetrix microarray platform to screen the pro-apoptotic effects induced by the expression of ORF2 protein in human hepatic cell lines (Huh7). The Huh7 cells were transduced either with recombinant adenovirus encoding the HEV ORF2 (Ad-ORF2) or an adenovirus encoding the green fluorescent protein (Ad-GFP). The array results consistently showed an ORF2 specific induction of mRNA corresponding to the chaperones Hsp72, Hsp70B’ and co-chaperone Hsp40. These studies provide further mechanisms of the ER stress mediated pro apoptotic effects caused by the ORF2 protein and its potential role for the activation of anti-apoptotic activity of the host cell. We used microarray to screen the host genes were regulated by the expression of the hepatitis E virus capsid protein. Huh7 cells transduced with Ad-GFP (control) or with Ad-HEV ORF2.
2012-12-01 | E-GEOD-29061 | biostudies-arrayexpress
Project description:Analysis of human liver cell line (Huh7) infected with HEV ORF3 expressing (Ad-orf3-egfp) and control recombinant adenovirus (Ad-egfp). Hepatitis E virus ORF3 protein (pORF3) is known to modulate the host cell. Results provide insight into the role of this protein for HEV infection and pathogenesis.
2010-12-01 | GSE23412 | GEO
Project description:Analysis of human liver cell line (Huh7) infected with HEV ORF3 expressing (Ad-orf3-egfp) and control recombinant adenovirus (Ad-egfp). Hepatitis E virus ORF3 protein (pORF3) is known to modulate the host cell. Results provide insight into the role of this protein for HEV infection and pathogenesis. The gene expression experiment of Huh7 hepatoma cell line infected with ORF3 expressing recombinant adenoviruses (Ad-orf3-egfp) and with control recombinant adenoviruses (Ad-egfp) was performed in replicates of three.
2010-12-01 | E-GEOD-23412 | biostudies-arrayexpress
Project description:Background: Hepatitis E Virus (HEV) is a new causative agent of chronic hepatitis in solid organ transplant recipients in Europe. Factors associated with the occurrence and persistence of chronic HEV infection remain largely unknown but chronic evolution seems to be the consequence of host’s immunological factors rather than of viral factors. Method: In a prospective case-control study, we have determined in whole blood of chronically HEV-infected kidney-transplant recipients the host response using microarray technology. Results: Chronically HEV-infected kidney-transplant recipients exhibited a specific transcriptional program, in which interferon effectors were prominent. The intensity of expression of each signature’s gene was significantly lower in patients who were subsequently cleared of HEV than in patients who were not. Furthermore, in patients who were cleared of HEV, a higher expression of these genes was associated with a longer delay until HEV clearance. Conclusions: The specific transcriptional program determined in chronically HEV-infected kidney-transplant recipients suggests an activation of type I interferon response. Intensity of interferon-stimulated genes expression could be useful to forecast the outcome of infection. High expression of interferon-stimulated genes could signify a dysregulation in the interferon response that might favour the persistence of the HEV infection. Trial’s registration number: NCT01090232; Registry’s URL: http://clinicaltrials.gov/ct2/show/study/NCT01090232?term=kidney+transplant+recipients&cntry1=EU%3AFR&rank=2
2013-01-29 | GSE36539 | GEO