Abstract
Hepatitis E is the most common type of acute hepatitis prevalent worldwide. The open reading frame 3 protein of HEV (HEV ORF3) is proposed to create a favorable environment for viral replication and pathogenesis. However, the mechanisms by which HEV overcomes the effects of host immunity, particularly the role of ORF3, remain to be established. Expression of IFNα and IFNβ in supernatant and cell samples was examined via ELISA and quantitative RT-PCR. The protein levels of specific signaling factors in cells overexpressing HEV ORF3 were examined via western blot. Analyses of cells transfected with vectors expressing ORF3 demonstrated that HEV ORF3 significantly impairs the generation of endogenous type I interferon through downregulating TLR3 and TLR7 as well as their corresponding downstream signaling pathways. Moreover, inhibition of NFκB, JAK/STAT and JNK/MAPK signaling pathways contributed significantly to suppression of increased levels of TLR7. Levels of p-P65, p-STAT1 and p-JNK were markedly impaired in ORF3-expressing cells, even upon treatment with the respective agonists. HEV ORF3 inhibits the production of endogenous type I interferon through downregulation of TLR3 and TLR7. Furthermore, suppression of TLR7 is achieved through impairment of multiple signaling pathways, including NFκB, JAK/STAT and JNK/MAPK.
Highlights
Hepatitis E virus (HEV) is the most common causative agent of acute hepatitis worldwide, often leading to chronic hepatitis or fulminant hepatic failure in immunocompromised individuals and pregnant women[1,2]
HEV ORF3 impairs the generation of endogenous type I interferon in host cells through downregulating TLR3 and TLR7
To ascertain whether HEV ORF3 can regulate innate immunity and generation of endogenous interferon of host cells, adenoviruses and plasmid vectors expressing ORF3 protein were transfected into THP1 and LO2 cell lines, respectively, and expression levels of type I interferon detected
Summary
Hepatitis E virus (HEV) is the most common causative agent of acute hepatitis worldwide, often leading to chronic hepatitis or fulminant hepatic failure in immunocompromised individuals and pregnant women[1,2]. All three ORFs of HEV regulate numerous cellular signaling pathways and inhibit host immune responses to promote survival of infected cells[6]. A number of studies suggest a key role of HEV ORF3 in manipulating various host cell processes during viral infection and propagation. The mechanism by which HEV overcomes the effects of cellular immunity in host cells, in particular, the role of ORF3, are yet to be established. Xu and co-workers showed that ORF3 transiently activates nuclear factor kappa B (NFκB) signaling at the early infection and inhibits this pathway at the late phase to create a favorable replication environment for HEV9. The type I interferon (IFN) system, which includes IFNα and IFNβ mainly induced by TLRs, is an innate immune response. HEV downregulates RIG-I helicase-like receptor-mediated IFN induction and employs MAVS in curtailing the host inflammatory response[10]
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