MiR-10a-5p-Mediated Syndecan 1 Suppression Restricts Porcine Hemagglutinating Encephalomyelitis Virus Replication

Abstract

Porcine hemagglutinating encephalomyelitis virus (PHEV) is a single-stranded RNA coronavirus that causes nervous dysfunction in the infected hosts and leads to widespread alterations in the host transcriptome by modulating specific microRNA (miRNA) levels. MiRNAs contribute to RNA virus pathogenesis by promoting antiviral immune response, enhancing viral replication, or altering miRNA-mediated host gene regulation. Thus, exploration of the virus-miRNA interactions occurring in PHEV-infected host may lead to the identification of novel mechanisms combating the virus life cycle or pathogenesis. Here, we discovered that the expression of miR-10a-5p was constitutively up-regulated by PHEV in both the N2a cells in vitro and mice brain in vivo. Treatment with miR-10a-5p mimics allowed miR-10a-5p enrichment and resulted in a significant restriction in PHEV replication, suggesting widespread negative regulation of the RNA virus infection by miR-10a-5p. The outcomes were also evidenced by miR-10a-5p inhibitor over-expression. Luciferase reporter, quantitative real-time PCR (qRT-PCR), and western blotting analysis further showed that Syndecan 1 (SDC1), a cell surface proteoglycan associated with host defense mechanisms, acts as a target gene of miR-10a-5p during PHEV infection. Naturally, siRNA-mediated knockdown of SDC1 leads to a reduction in viral replication, implying that SDC1 expression is likely a favorable condition for viral replication. Together, the findings demonstrated that the abundant miR-10a-5p leads to downstream suppression of SDC1, and it functions as an antiviral mechanism in the PHEV-induced disease, providing a potential strategy for the prevention and treatment of PHEV infection in the future work.

Prediction and Analysis of SARS-CoV-2-Targeting <i>microRNA</i> in Human Lung Epithelium

“…While there are no agomir-based drugs currently approved for coronavirus infections, several studies have reported positive results for this drug class in the in vivo protection against influenza A (H1N1) [13] and hepatitis B [33] viral infections. Notably, one study found that an agomir of miR-10a-5p was able to prevent the replication of porcine hemagglutinating encephalomyelitis virus (PHEV) in mice [34]. Although PHEV does not pose a threat to humans, it is part of the coronavirus family [35], suggesting that agomir therapy may have efficacy against other coronaviruses, notably SARS-CoV-2, MERS-CoV, and SARS-CoV.…”

Prospects for RNAi Therapy of COVID-19

“…Past investigations on non-coding microRNAs (miRs) have opened up new possibilities particularly into development of malignancies and their therapy, but this remains a vastly understudied area in the case of SARS-CoV. The significant changes in endogenous miR profiles of cells transfected with porcine hemagglutinating encephalomyelitis virus (HEV), for example, have been noted ( Fan et al, 2020 ; Hu et al, 2020 ). miR-1246 was recently linked to regulation of ACE2 expression in airway epithelium ( Zhang et al, 2020b ) and several miRs have been predicted to bind to the SARS-CoV-2 genome ( Chen and Zhong, 2020 ).…”

“…Such miRs could serve as RNAi targets and/or might be deployed directly (either as miR mimics or anti-miRs), or indirectly as a result of modulation with pharmacological agents. Identifying the pertinent miRs and revealing their mechanistic involvement is bound to provide effective leads not predicted before, such as the case of Syndecan 1 involvement, which is regulated by miR-10a-5p, and whose mimic significantly altered the course of HEV replication ( Hu et al, 2020 ).…”

The potential use of microRNAs as a therapeutic strategy for SARS-CoV-2 infection

“…For example, porcine hemagglutinating encephalomyelitis virus (PHEV), a member of the genus Betacoronavirus that causes nervous system disorders in its host, has been reported to constitutively upregulate the expression of miR-10a-5p in host cells. Treatment with an miR-10a-5p mimic leads to enrichment of miR-10a-5p and a substantial decrease in PHEV replication, suggesting extensive negative control of RNA virus infection by miR-10a-5p [ 54 ]. It was also found that miR-21a-5p was significantly upregulated in the brains of mice, leading to negative regulation of Caskin1 (CASK-interactive protein1) through direct binding to the 3′-UTR of this gene.…”