Hepatitis E virus‐encoded microRNA promotes viral replication by inhibiting type I interferon

Abstract

MicroRNAs (miRNAs), the non-coding RNAs of ~22 nucleotides (nt) in length, play a vital role in regulating viral replication. Hepatitis E virus (HEV), a singlestranded RNA virus, is a predominant pathogen of acute hepatitis worldwide.Virus-encoded miRNAs regulate the viral life cycle and escape from the host innate immune system. However, it is rarely known about HEV-encoded miRNA (HEV-miR-A6). In the present study, HEV-miR-A6 was screened by microarray, and further identified in vivo and in vitro. HEV-miR-A6 originated from the methylase (MeT) of HEV open reading frame 1 (ORF1) and was highly conserved in eight HEV genotypes. HEV-miR-A6 expression was growing during HEV replication, and significantly increased in acute hepatitis E patients than convalescence patients. Furthermore, HEV-miR-A6 was specifically detected in liver, spleen, kidney and colon by in situ hybridization. To identify the specificity of HEV-miR-A6, its mutants (HEV-miR-A6M1 and HEV-miR-A6M2) were constructed to change the stem-loop structure. Interestingly, over-expression of HEV-miR-A6 or HEV-miR-A6M1 significantly facilitated viral replication, while HEV-miR-A6M2, another mutant completely changed the stem-loop structure was invalid. SIRP-α, a candidate target gene of HEV-miR-A6, was activated when HEV-miR-A6 over-expressed to inhibit the phosphorylation of IRF3, and subsequently suppressed the expression of type I interferon β (IFN-β). The promotion of viral replication by HEV-miR-A6 further identified in vivo. Significant suppression of IFN-β production in the serum of HEV-infected mice pre-treated with How to cite this article: Qian Z, Yang C, Xu L, et al. Hepatitis E virus-encoded microRNA promotes viral replication by inhibiting type I interferon.

Hepatitis E Virus Infection Caused Elevation of Alanine Aminotransferase Levels in a Patient with Chronic Hepatitis B and Choledocholithiasis

“…Li et al [41] reported that the anti-cancer drug gemcitabine inhibited HEV through inducing an interferon-like response via the activation of STAT1 phosphorylation. Human liver-derived organoids [42,43] and microRNA signatures in HEV infection [44,45] could be helpful for the development of antivirals against HEV infection.…”

Pathogenesis and clinical features of severe hepatitis E virus infection

“…HEV encodes a microRNA (miRNA), HEV-miRNA-A6, which can inhibit the phosphorylation of IRF3, thereby reducing the production of type I IFNs[ 53 ]. Moreover, HEV ORF-1 interferes with the recognition of viral RNA by RIG-I and impairs the activation of the JAK-STAT signaling pathway by inhibiting STAT-1 activation and nuclear translocation[ 54 , 55 ].…”

“…Several viruses, including HEV, are known to encode miRNAs[ 53 ]. To illustrate, HEV-miR-A6 aids viral replication and deters the host’s innate immune response by inhibiting the expression of type I IFNs[ 53 ]. Additionally, the cellular miR-122 could boost HEV replication[ 144 ].…”

Micro RNAs—The Small Big Players in Hepatitis E Virus Infection: A Comprehensive Review

“…The production of HEV-miR-A26 by HEV was confirmed in the cell transfection model, animal infection model and measurement of increasing miR-A26 levels in patient’s serum from an acute phase, vs. patients in convalescence phase of HEV infection. It is hypothesized that the main function of HEVmiR-A26 is to facilitate virus replication by suppressing the production of IFN-β [ 54 ].…”