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 single‐stranded 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 HEV‐miR‐A6 was observed. In summary, HEV‐miR‐A6 activates SIRP‐α to promote viral replication by inhibition of IFN‐β expression.