Potential Role of MicroRNAs in the Regulation of Antiviral Responses to Influenza Infection

Abstract

Influenza is a major health burden worldwide and is caused by influenza viruses that are enveloped and negative stranded RNA viruses. Little progress has been achieved in targeted intervention, either at a population level or at an individual level (to treat the cause), due to the toxicity of drugs and ineffective vaccines against influenza viruses. MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in gene expression, cell differentiation, and tissue development and have been shown to silence viral replication in a sequence-specific manner. Investigation of these small endogenous nucleotides may lead to new therapeutics against influenza virus infection. Here, we describe our current understanding of the role of miRNAs in host defense response against influenza virus, as well as their potential and limitation as new therapeutic approaches.

Keywords: immune responses; infection; inflammation; influenza virus; microRNA.

Figure 1

MicroRNA (miRNA) processing and function. MiRNA is first transcribed as long hairpin primary RNA (pri-miRNA) by RNA polymerase II and cleaved into hairpin precursor miRNA (pre-miRNA) by the complex Drosha-DGCR8 in nucleus. This pre-miRNA then is exported to the cytoplasm by exportin-5 protein and cleaved to two strands by endoribonuclease Dicer, one strand becomes a mature miRNA and silence target mRNAs through mRNA degradation or translation repression and the other is degraded.

Figure 2

(A) Influenza structure: a lipid bilayer envelope containing glycoproteins M1 and M2 ion channel. Hemagglutinin and neuraminidase proteins on the outside of the envelope. Eight RNA genome segments inside the envelope encoding for three polymerase complex proteins (PB1, PB2, and PA), nucleoproteins (NPs), M1 and M2 matrix proteins, and non-structural proteins (NS1, NS2, PA-X and PB1-F2). (B) Cellular microRNAs (miRNAs) modulate influenza replication. Host cellular miRNAs inhibit influenza replication through targeting viral RNAs and proteins that are essential for influenza replication and translation such as PB1, M1, and nucleoprotein.

Figure 3

MicroRNAs (miRNAs) regulate innate host immune response against influenza infection by targeting intracellular signaling pathways. Upon infection, influenza can activate different intracellular signaling pathways such as NF-κB, RIG-like receptor (RIG-I), TNF receptor-associated factors (TRAFs), and interferon regulatory factors (IRFs) through different pattern recognition receptors including TLR3, TLR4, TLR7/8. TLR3 and TR7/8 that recognize double stranded RNA and single-stranded RNA in the endosome, respectively. The ligand for TLR4 in influenza virus is unknown; however, it is thought to be activated by the damage-associated molecular patterns molecules released in influenza virus-infected cells and trigger TLR4-MyD88-signaling pathways. Induction of these TLRs can lead to activation of NF-κB, IRF 3, 5, and 7 and induce expression of type-I and -II IFN, IFN-stimulated genes, and inflammatory genes. Some miRNAs regulate these pathways through targeting critical components such as TRAF6, IRF3, IRF5, IFR7, interleukin-1 receptor-associated kinase 1, and IκBβ. Within the infected cells, RIG-I detects the 5-triphosphorylated RNA of replicating viral genomes in cytosol and associates with mitochondrial antiviral signaling protein (MAVS) to induce pro-inflammatory cytokines and type-I IFN. miRNAs can modulate this pathway by directly targeting RIG-I, MAVS, or NF-κB-inducing kinase.