The Capsid Protein of Hepatitis E Virus Inhibits Interferon Induction via Its N-terminal Arginine-Rich Motif.

Shaoli Lin,Zexu Ma,Yan-Jin Zhang,Yuchen Nan,Liping Yang,Yonglin Yang

doi:10.3390/v11111050

Abstract

Hepatitis E virus (HEV) causes predominantly acute and self-limiting hepatitis. However, in HEV-infected pregnant women, the case fatality rate because of fulminant hepatitis can be up to 30%. HEV infection is zoonotic for some genotypes. The HEV genome contains three open reading frames: ORF1 encodes the non-structural polyprotein involved in viral RNA replication; ORF2 encodes the capsid protein; ORF3 encodes a small multifunctional protein. Interferons (IFNs) play a significant role in the early stage of the host antiviral response. In this study, we discovered that the capsid protein antagonizes IFN induction. Mechanistically, the capsid protein blocked the phosphorylation of IFN regulatory factor 3 (IRF3) via interaction with the multiprotein complex consisting of mitochondrial antiviral-signaling protein (MAVS), TANK-binding kinase 1 (TBK1), and IRF3. The N-terminal domain of the capsid protein was found to be responsible for the inhibition of IRF3 activation. Further study showed that the arginine-rich-motif in the N-terminal domain is indispensable for the inhibition as mutations of any of the arginine residues abolished the blockage of IRF3 phosphorylation. These results provide further insight into HEV interference with the host innate immunity.

Highlights

Hepatitis E virus (HEV) is the causative agent of liver inflammation that mainly presents as acute and self-limiting hepatitis [1]
The immunofluorescence assay (IFA) results showed that in the Kernow-infected HepG2/C3A cells, only the capsid protein could be detectable, while ORF1 and ORF3 products were below the detection level (Figure 1C), indicating the abundance of the capsid protein
To verify the antibodies against the individual viral proteins, HEV helicase, ORF2, and ORF3 were transiently expressed in HeLa cells

Summary

Introduction

Hepatitis E virus (HEV) is the causative agent of liver inflammation that mainly presents as acute and self-limiting hepatitis [1]. In HEV-infected pregnant women, liver inflammation can be exacerbated to fulminant hepatitis and results in up to 30% case fatality [2]. Chronic HEV infection with rapid progression in immunocompromised patients has been a challenge in many countries in recent years [3]. The transmission of HEV is mainly through contaminated drinking water or foods [1]. HEV is a single-stranded, positive-sense RNA virus of the family Hepeviridae [4]. HEV strains are classified into two genera: Orthohepevirus and Piscihepevirus. The genotype 1 and 2 are restricted to humans; genotype 3 and 4 cause zoonotic infections; genotype 5 and 6 are only reported to infect wild boars; genotype 7 and 8 are isolated from camels, while a sole case of human infection from genotype

Methods

Results

Conclusion