Hepatitis E virus persists in the presence of a type III interferon response

PLoS Pathogens

Xinlei Li¹  Xin Yin¹  Charuta Ambardekar¹  Zhimin Hu¹  Sébastien Lhomme¹  Zongdi Feng¹ 

[1] Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America

关键词: Hepatitis E virus;    Interferons;    Hepatitis C virus;    Transfection;    Hepatitis A virus;    Luciferase;    Viral replication;    Phosphorylation;   

DOI  :  10.1371/journal.ppat.1006417

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The RIG-I-like RNA helicase (RLR)-mediated interferon (IFN) response plays a pivotal role in the hepatic antiviral immunity. The hepatitis A virus (HAV) and the hepatitis C virus (HCV) counter this response by encoding a viral protease that cleaves the mitochondria antiviral signaling protein (MAVS), a common signaling adaptor for RLRs. However, a third hepatotropic RNA virus, the hepatitis E virus (HEV), does not appear to encode a functional protease yet persists in infected cells. We investigated HEV-induced IFN responses in human hepatoma cells and primary human hepatocytes. HEV infection resulted in persistent virus replication despite poor spread. This was companied by a type III IFN response that upregulated multiple IFN-stimulated genes (ISGs), but type I IFNs were barely detected. Blocking type III IFN production or signaling resulted in reduced ISG expression and enhanced HEV replication. Unlike HAV and HCV, HEV did not cleave MAVS; MAVS protein size, mitochondrial localization, and function remained unaltered in HEV-replicating cells. Depletion of MAVS or MDA5, and to a less extent RIG-I, also diminished IFN production and increased HEV replication. Furthermore, persistent activation of the JAK/STAT signaling rendered infected cells refractory to exogenous IFN treatment, and depletion of MAVS or the receptor for type III IFNs restored the IFN responsiveness. Collectively, these results indicate that unlike other hepatotropic RNA viruses, HEV does not target MAVS and its persistence is associated with continuous production of type III IFNs.

【 授权许可】

CC BY