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

Abstract

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.

The RNA genome of hepatitis E virus robustly triggers an antiviral interferon response

“…In immunocompromised patients, chronic infection has been widely reported, which is conceivably attributed to compromised innate and adaptive immunity . Consistently, a recent study reported that persistent HEV infection in cell culture does not activate type I IFN, although it was accompanied by a type III IFN response . In our study, we found that HEV RNA activates both type I and type III IFN responses, resulting in potent antiviral effects, which more likely reflected the infection phase with active virus–host interactions in HEV patients.…”

Immunity against hepatitis E virus infection: Implications for therapy and vaccine development

“…This suggests they have functional roles in HEV sensing and activation of the downstream anti‐viral signaling pathway . Consistently, inhibition of IRF3 phosphorylation, the key downstream signaling pathway of TLR3, RIG‐I and MDA5, notably increases HEV replication …”

“…RIG‐I and MDA5 are involved in the HEV‐induced IFN response . HEV induces predominantly a type III IFN response, rather than a type I IFN, to control viral growth .…”

“…RIG‐I and MDA5 are involved in the HEV‐induced IFN response . HEV induces predominantly a type III IFN response, rather than a type I IFN, to control viral growth . Furthermore, lack of both RIG‐I and TLR3 signaling facilitates HEV replication which can be reversed by reconstitution of RIG‐I and TLR3 .…”

Type III Interferons in Viral Infection and Antiviral Immunity

“…Regardless of IFN subtypes, RIG-I activates two distinct categories of ISGs, one JAK-STAT-dependent and the other JAK-STAT-independent, which coordinately contribute to the antiviral immune response to HEV infection [92]. However, persistent activation of the JAK-STAT-dependent signaling pathway enables HEV-infected cells to resist exogenous IFN treatment, while the depletion of IFN-λ receptors or MAVS (mitochondria antiviral signaling protein) resorts to the antiviral immune response induced by IFN, suggesting that the persistent presence of IFN-λ benefits the establishment of HEV infection [93]. Together with a recent report of antiviral immune activities mediated by IFN-λ, we still lack important pieces of information on basic IFN-λ functions.…”