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

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.

RIG-I样RNA解旋酶（RIG-I-like RNA helicase，RLR）介导的干扰素（interferon，IFN）应答在肝脏抗病毒免疫中发挥关键作用。甲型肝炎病毒（hepatitis A virus，HAV）与丙型肝炎病毒（hepatitis C virus，HCV）可通过编码病毒蛋白酶，切割RLR的共同信号接头分子——线粒体抗病毒信号蛋白（mitochondrial antiviral signaling protein，MAVS）——来拮抗该干扰素应答。然而，第三种嗜肝RNA病毒——戊型肝炎病毒（hepatitis E virus，HEV）——虽似乎不编码功能性蛋白酶，却可在感染细胞中持续存在。本研究在人肝癌细胞系与原代人肝细胞中，探究了HEV诱导的IFN应答。尽管病毒传播能力较弱，HEV感染仍可引发持续的病毒复制。该过程伴随III型IFN应答，该应答可上调多种IFN刺激基因（IFN-stimulated genes，ISGs），但几乎无法检测到I型IFN。阻断III型IFN的产生或信号通路，会降低ISG的表达水平，并增强HEV的复制能力。与HAV和HCV不同，HEV并不会切割MAVS；在HEV复制的细胞中，MAVS的蛋白分子量、线粒体定位及功能均未发生改变。敲低MAVS或MDA5（对RIG-I的干预效果相对较弱），同样会减少IFN的产生，并增加HEV的复制水平。此外，JAK/STAT信号通路的持续活化会使感染细胞对外源IFN处理产生耐受，而敲低MAVS或III型IFN受体则可恢复细胞的IFN应答能力。综上，本研究结果表明，与其他嗜肝RNA病毒不同，HEV并不靶向MAVS，其持续感染与III型IFN的持续产生密切相关。