Analysis of Antiviral Response in Human Epithelial Cells Infected with Hepatitis E Virus
Open Access
- 9 May 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (5), e63793
- https://doi.org/10.1371/journal.pone.0063793
Abstract
Hepatitis E virus (HEV) is a major cause of enterically transmitted acute hepatitis in developing nations and occurs in sporadic and epidemic forms. The disease may become severe with high mortality (20%) among pregnant women. Due to lack of efficient cell culture system and small animal model, early molecular events of HEV infection are not yet known. In the present study, human lung epithelial cells, A549, were infected with HEV to monitor expression levels of genes/proteins in antiviral pathways. Both live and UV inactivated virus elicited robust induction of inflammatory cytokines/chemokines such as IL-6, IL-8, TNF-α, and RANTES within 12 h of infection. Cells exposed to soluble capsid protein showed no induction suggesting the capsid structure and not the protein being detected as the pathogen pattern by cells. A delayed up-regulation of type I interferon genes only by the live virus at 48 h post HEV infection indicated the need of virus replication. However, absence of secreted interferons till 96 h suggested possible involvement of post-transcriptional regulation of type I IFN expression. HEV infected cells showed activation of both NF-κB and IRF3 transcription factors when seen at protein levels; however, reporter gene assays showed predominant expression via NF-κB promoter as compared to IRF3 promoter. Knockdown experiments done using siRNAs showed involvement of MyD88 and TRIF adaptors in generating antiviral response thus indicating role of TLR2, TLR4 and TLR3 in sensing viral molecules. MAVS knockdown surprisingly enhanced only proinflammatory cytokines and not type I IFNs. This suggested that HEV not only down-regulates RIG-I helicase like receptor mediated IFN induction but also employs MAVS in curtailing host inflammatory response. Our findings uncover an early cellular response in HEV infection and associated molecular mechanisms suggesting the potential role of inflammatory response triggered by HEV infection in host immune response and pathogenesis.This publication has 41 references indexed in Scilit:
- Detection of Negative-Sense RNA in Packaged Hepatitis E Virions by Use of an Improved Strand-Specific Reverse Transcription-PCR MethodJournal of Clinical Microbiology, 2012
- Molecular virology of hepatitis E virusVirus Research, 2011
- Pathogenesis of Hepatitis E Virus and Hepatitis C Virus in Chimpanzees: Similarities and DifferencesJournal of Virology, 2010
- Release of Genotype 1 Hepatitis E Virus from Cultured Hepatoma and Polarized Intestinal Cells Depends on Open Reading Frame 3 Protein and Requires an Intact PXXP MotifJournal of Virology, 2010
- Hepatitis E Virus (HEV) Strains in Serum Samples Can Replicate Efficiently in Cultured Cells Despite the Coexistence of HEV Antibodies: Characterization of HEV Virions in Blood CirculationJournal of Clinical Microbiology, 2010
- Pattern Recognition Receptors and InflammationCell, 2010
- TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activityNature, 2007
- ORF3 Protein of Hepatitis E Virus Is Not Required for Replication, Virion Assembly, or Infection of Hepatoma Cells In VitroJournal of Virology, 2006
- Pathogen Recognition and Innate ImmunityCell, 2006
- De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signallingNature, 2004