Up-regulation of microRNA-203 in influenza A virus infection inhibits viral replication by targeting DR1

Sen Zhang,Junfeng Li,Xiaoyan Wu,Qingyu Zhu,Xiaoping Kang,Yusen Zhou,Jing Li,Yi Hu,Yuchang Li,Yinhui Yang

doi:10.1038/s41598-018-25073-9

Abstract

MicroRNAs (miRNAs) are small noncoding RNA molecules that play important roles in various biological processes. Much evidence shows that miRNAs are closely associated with numerous virus infections; however, involvement of cellular miRNAs in influenza A virus (IAV) infection is unclear. Here, we found that expression of miR-203 was up-regulated markedly via two different mechanisms during IAV infection. First, we examined the effects of type I interferon induced by IAV on direct activation of miR-203 expression. Next, we showed that DNA demethylation within the miR-203 promoter region in A549 cells induced its up-regulation, and that expression of DNA methyltransferase 1 was down-regulated following H5N1 virus infection. Ectopic expression of miR-203 in turn inhibited H5N1 virus replication by targeting down-regulator of transcription 1 (DR1), which was identified as a novel target of miR-203. Silencing DR1 in miR-203 knockout cells using a specific siRNA inhibited replication of the H5N1 virus, an effect similar to that of miR-203. In summary, the data show that host cell expression of miR-203 is up-regulated upon IAV infection, which increases antiviral responses by suppressing a novel target gene, DR1. Thus, we have identified a novel mechanism underlying the relationship between miR-203 and IAV infection.

Highlights

MicroRNAs are post-transcriptional regulators that play important roles in a number of biological processes, including cell proliferation, differentiation, apoptosis, stress responses, and regulation of inflammatory pathways[1]
A549 cells were infected with different subtypes of Influenza A virus (IAV) (H1N1 (501), multiplicity of infection (MOI) = 5; H1N1 (PR8), MOI = 5; H3N2, MOI = 5; H5N1, MOI = 2; and H7N9, MOI = 5) for 24 or 48 h
The results showed that miR-203 was up-regulated (Fig. 2E), a result consistent with that observed in A549 cells (Fig. 2B); this was further confirmation that type I IFN plays an important role in inducing miR-203

Summary

Introduction

MicroRNAs (miRNAs) are post-transcriptional regulators that play important roles in a number of biological processes, including cell proliferation, differentiation, apoptosis, stress responses, and regulation of inflammatory pathways[1]. Alteration of cellular miRNAs can have two different results: viruses change the intracellular environment to evade antiviral immune responses, or host cells trigger antiviral defenses that affect viral replication[10]. Studies show that expression of more than 100 host miRNAs is altered during infection; these miRNAs promote or inhibit viral replication[14,15]. Some host miRNAs target IAV genes directly to inhibit replication. Cellular miR-584-5p and miR-1249 are down-regulated upon H5N1 virus infection; these miRNAs target the PB2 gene to inhibit viral replication[16]. We aimed to further identify candidate miRNAs that participate in host immune responses to IAV infection. The data presented increase our understanding of the role of host miRNA in the stress response to IAV infection

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Conclusion