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About the Authors:
Xin Yin
Affiliation: Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
Xinlei Li
Affiliation: Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
Charuta Ambardekar
Affiliation: Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
Zhimin Hu
Affiliation: Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
ORCID http://orcid.org/0000-0003-3958-2346
Sébastien Lhomme
Affiliation: Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
ORCID http://orcid.org/0000-0001-7908-1576
Zongdi Feng
* E-mail: [email protected]
Affiliations Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, United States of America
ORCID http://orcid.org/0000-0001-7913-1027Abstract
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...