Project description:What happens in cells infected with HEV is largely unknown. We used a recently established genotype 3 HEV cell culture system and profiled the host responses by RNA-seq.
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.
Project description:We aimed to identify interferon (IFN)-regulated genes that are differentially expressed during chronic HEV infection in human hepatocytes, the main site of HEV replication, using HepaRG cells.
Project description:We aimed to identify interferon (IFN)-regulated genes that are differentially expressed during chronic HEV infection in human hepatocytes, the main site of HEV replication, using HepaRG cells.
Project description:Alport syndrome is a glomerular disease. To understand the disease progression of alport syndrome and potential therapeutical effects of hEV derived from AFSCs, we performed spatial transcriptomics to profile the heterogeniety of cell populations in kidneys of mouse of AS through disease progression and hEV treated AS mice as well. Our analysis sheds light on key functional parts of the kidney responsible in disease progression as well as potential targets of hEV therapy.
Project description:We aimed to identify interferon (IFN)-regulated genes that are differentially expressed during chronic HEV infection in human hepatocytes, the main site of HEV replication, using HepaRG cells. We have performed a preliminary screen using whole-cell RNA extracts prepared from HepaRG mock-infected or infected cells to determine whether HEV was able to trigger an IFN response. Different multiplicities of infection (MOI) (10 and 100 genome equivalent (GE)/cell) and time points (D+7, D+14, D+26, D+40, D+72 and D+100) were analyzed using the PCR array. We have also treated HepaRG cells after overnight treatment with IFN-β to confirm the ability of HepaRG to respond to IFN-I treatment.
Project description:We aimed to identify interferon (IFN)-regulated genes that are differentially expressed during HEV infection in swine liver tissues.
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.
