The intestinal crypt is a potential reservoir for hepatitis E virus infections
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE303209 | GEO | 2026/02/25
REPOSITORIES: GEO
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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:The liver, and more precisely hepatocytes, can be infected by several viruses such as hepatitis B (HBV), hepatitis D (HDV), hepatitis C (HCV), hepatitis E (HEV) viruses, with chronic infection leading to end-stage liver diseases. Since no in vitro model allowing multi-infections with the four viruses is reported, limited data are available on the interplay between those viruses as well as on the potential cross-reactivity of antivirals in multi-infection cases. Here we showed that HuH7.5-NTCP cells can be partially differentiated into hepatocyte-like cells and genuinely replicate HBV, HDV, HCV and HEV for at least 4 weeks after mono or multiple infections. Additionally, we recapitulated the effect of known antivirals and found that FXR-agonists, also strongly inhibited HEV replication. Using HEV infected HuHep mice, we confirmed the antiviral effect of Vonafexor, the FXR agonist clinical candidate currently tested against HBV and HDV, highlighting FXR-ligands as potential broad acting antivirals. Here, we set-up the first in vitro model allowing multi-infections with hepatitis viruses that can be used for broad drug screening.
2025-04-23 | GSE288204 | GEO
Project description:Background & Aims: Other than hepatitis B or C virus infection, Hepatitis E virus (HEV) infection is generally asymptomatic or leads to acute and self-limiting hepatitis. However, the mechanism of host cell defense against HEV is unclear. Viruses are known to perturb host cellular metabolism to enable their replication and spread. AMP-activated protein kinase (AMPK) activation is crucial for the regulation of cell homeostasis. We thus investigated the role of AMPK in HEV infection. Methods: Huh7, THP1 and HepG2 cells inoculated with infectious HEV viral particle or Huh7 and organoids transfected with in vitro generated subgenomic or full-length GT3 (Kernow-C1 p6 strain) HEV RNA, namely, p6Luc or p6 were used to model HEV infection. Viral replication and genes expression were quantified. Activation of AMPK, innate immune response and autophagy process were assessed. Results: We found HEV infection can trigger AMPK activation by phosphorylation of AMPK at threonine 172 by transfecting HEV viral RNA into host cells or inoculating host cells with infectious HEV viral particle. The activation of AMPK is associated with HEV induced mitochondrial damage and ATP deficiency. Pharmacological activation of AMPK using 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) attenuated HEV replication, which was reversed by an AMPK inhibitor (compound C). Lentivirus-mediated knockdown of AMPK provided further evidence that AMPK has an antiviral effect on HEV replication. These results suggested that AMPK activation is a potent strategy of host cells for HEV clearance. Consistent with its antiviral effect, AMPK activation potentiated the expression of genes with antiviral properties (e.g., IFNs, ISG15, and IRF9) and inhibited inflammatory response (e.g., NF-KB NLRP3 and IL-1β). Meanwhile, HEV and activated AMPK also decreased autophagosome accumulation by decreasing induction of autophagy and autophagic degradation. Consistently, we found inhibition of AMPK efficiently augmented HEV induced autophagosome accumulation, evidenced by a marked increase in LC3II. Our previous study showed that rapamycin, an activator of autophagic induction by inhibiting mTOR, and Bafilomycin A1, an inhibitor of autophagic degradation, has a potent pro-HEV effect under AICAR treatment. Moreover, Wortmannin inhibiting autophagic induction recover AMPK inhibitor induced HEV replication. Together, these results suggested that HEV induced AMPK activation can serve to protect HEV infected cells from HEV infection by attenuating autophagosome and promoting innate immunity. Conclusions: Here we show that HEV infection can activate AMPK phosphorylation, which attenuates autophagosome accumulation and increases innate immune signaling. Thus, the AMPK activation in response to HEV infection is critical in host cells for rapid viral clearance by coordinating autophagic process and establishing persistent antiviral immunity.
2024-03-31 | GSE262469 | GEO
Project description:Hepatitis E virus (HEV) infection, one of the most common forms of hepatitis worldwide, is often associated with extrahepatic, particularly renal, manifestations. However, the underlying mechanisms are incompletely understood. Here, we report the development of a de novo immune complex-mediated glomerulonephritis (GN) in a kidney transplant recipient with chronic hepatitis E. Applying immunostaining, electron microscopy, and mass spectrometry after laser-capture microdissection, we show that GN developed in parallel with increasing glomerular deposition of a non-infectious, genome-free and non-glycosylated HEV open reading frame 2 (ORF2) capsid protein. No productive HEV infection of kidney cells is detected. Patients with acute hepatitis E display similar but less pronounced deposits. Our results establish a link between the production of HEV ORF2 protein and the development of hepatitis E-associated GN. The formation of glomerular IgG-HEV ORF2 immune complexes discovered here provides a mechanistic explanation of how the actually hepatotropic HEV can cause variable renal manifestations. These findings directly provide a tool for etiology-based diagnosis of hepatitis E-associated GN as a distinct entity and suggest therapeutic implications.
2025-01-18 | PXD055348 | Pride
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: 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:Hepatitis E virus (HEV) is a globally prevalent pathogen that causes 20 million infections and 60,000 fatalities annually, endangering particularly pregnant women and immunosuppressed individuals. Liver cirrhosis, which results from advanced fibrosis, is the primary symptom and leading mortality cause in chronic hepatitis E patients. However, the causation and process of liver fibrosis triggered by chronic HEV infection remain poorly understood. Here, we unexpectedly discovered that the viral multiple-domain replicase (ORF1) undergoes unique ubiquitin-proteasomal processing in HEV replicon hepatocytes, HEV-infected gerbil livers, and HEV-infected patient livers, which follows a CHIP-mediated K48 ubiquitination and produces the HEV-Derived Smad Activator (HDSA). Lacking putative helicase and RNA polymerase domains, this enriched viral polypeptide in hepatocytes and gerbil livers is non-HSP90-bound, stable, and exhibits exclusively nuclear localization. Surprisingly, HDSA markedly potentiates the fibrogenic TGF-β/Smad pathway in livers by facilitating promoter binding and coactivator recruitment of SMAD3, leading to profound liver fibrotic symptoms and damage. Thus, we have identified the first viral protein derived from the unique proteasomal processing of the host, defined its notable role in liver fibrosis, and highlighted the nature of complex host-HEV interactions that drives HEV pathogenesis.
2024-08-01 | GSE251924 | GEO
Project description:Hepatitis E virus (HEV) infections are one of the most common causes of acute viral hepatitis, annually causing over 3 million symptomatic cases and 70,000 deaths worldwide. Historically, HEV was described as a hepatotropic virus, but has recently been associated with various extrahepatic manifestations including neurological disorders such as Guillain-Barré syndrome and neuralgic amyotrophy. However, the underlying pathogenesis of these neurological diseases remains largely unknown. The aim of this study was to investigate extrahepatic HEV manifestations in a neuronal model system using human induced primary neurons (iPNs). Renal epithelial cells from human urine were reprogrammed to induced pluripotent stem cells (iPSCs) to generate neuronal progenitor cells, which were subsequently differentiated into iPNs over 21 days. These iPNs supported HEV infection preferentially in neurite-bearing cells. Transcriptional profiling of the neuronal development process as well as viral infection dynamics in iPNs uncovered a lack of antiviral innate immune responses to HEV infection with only an intrinsic expression of distinct interferon-regulated genes (ISGs) and signaling molecules. Viral open reading frame 2 (ORF2) encoded capsid protein could be visualized by volumetric three-dimensional reconstitution within the neurites, which were reduced in length in an HEV inoculation-dependent manner. In conclusion, this neuron-derived human model system provides a powerful tool for studying extrahepatic manifestations of HEV infection. It further indicates a potential mechanism of pathogenesis driven by the interaction between host and viral factors.
2025-01-28 | GSE275473 | GEO
Project description:Lipid droplets (LDs) are dynamic organelles mediating lipid metabolism and diverse cellular processes. However, the interplay between hepatocyte LDs and hepatitis E remains poorly understood. Using targeted lipidomics and lipid profiling, we reveal in cellular and rodent models that hepatitis E virus (HEV) infection substantially increases hepatocyte LD biogenesis. Mechanistically, HEV pORF3 is a key LD biogenesis inducer and an essential factor for viral infectivity in vivo. pORF3 formed a unique LD organelle through its liquid-liquid phase-separation (LLPS) property, associating with enhancing cholesterol anabolic pathways, thereby facilitating the synthesis of triglycerides and cholesterol esters. Accordingly, deleting ORF3 or inhibiting LD biogenesis with LD-lowering agent atorvastatin substantially suppressed HEV infection in vivo. These findings position LDs as critical hubs for HEV infection, reveal lipid biogenesis as a crucial function of HEV infectivity, and suggest alternative strategies for HEV intervention.
2025-06-09 | GSE299317 | GEO