Abstract
Porcine reproductive and respiratory syndrome virus (PRRSV) is an Arterivirus that has been devastating the swine industry worldwide since the late 1980s. To investigate the impact of cellular microRNAs (miRNAs) on the replication of PRRSV, we screened 10 highly conserved miRNAs implicated in innate immunity or antiviral function and identified miR-125b as an inhibitor of PRRSV replication. Virus titer and western blot assays demonstrated that miR-125b reduced PRRSV replication and viral gene expression in a dose-dependent manner in both MARC-145 cell line and primary porcine alveolar macrophages. Mechanistically, miR-125b did not target the PRRSV genome. Rather, it inhibited activation of NF-κB, which we found to be required for PRRSV replication. PRRSV, in turn, down-regulated miR-125b expression post-infection to promote viral replication. Collectively, miR-125b is an antiviral host factor against PRRSV, but it is subject to manipulation by PRRSV. Our study reveals an example of manipulation of a cellular miRNA by an arterivirus to re-orchestrate host gene expression for viral propagation and sheds new light on targeting host factors to develop effective control measures for PRRS.
Highlights
MicroRNAs are small RNA molecules that regulate gene expression at the post-transcriptional level [1]
MARC-145 cells were transfected with the mimic or inhibitor of each miRNA (30 nM), followed by infection with Porcine reproductive and respiratory syndrome virus (PRRSV) (WUH3 strain) at an multiplicity of infection (MOI) of 0.1
We provide data demonstrating that miR-125b is a novel antiviral host factor against PRRSV, an economically important animal virus that devastates the swine industry worldwide
Summary
MicroRNAs (miRNAs, miRs) are small RNA molecules that regulate gene expression at the post-transcriptional level [1]. The resulting ,23-nucleotide double-stranded mature miRNA molecules load into RNA-induced silencing complexes (RISC) [4,5], where they act to repress mRNA translation or reduce mRNA stability by interacting with miRNA-recognition elements (MRE) within 39 untranslated region (UTR) of target genes [6]. Viral miRNAs may directly regulate viral and/or host cell gene expression to benefit the virus, and cellular miRNAs can influence viral replication and pathogenesis [13,14,15,16]. Instead of directly acting on VSV RNA, miR-155 was shown to target the expression of SOCS1, a negative regulator of type I interferon signaling, thereby indirectly enhancing the anti-viral state of the cell [26]. Defining the functions of miRNAs in regulating viral replication and pathogenesis may help identify new therapeutic approaches against viral diseases
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