Broad-Spectrum Inhibition of Respiratory Virus Infection by MicroRNA Mimics Targeting p38 MAPK Signaling

Abstract

The majority of antiviral therapeutics target conserved viral proteins, however, this approach confers selective pressure on the virus and increases the probability of antiviral drug resistance. An alternative therapeutic strategy is to target the host-encoded factors that are required for virus infection, thus minimizing the opportunity for viral mutations that escape drug activity. MicroRNAs (miRNAs) are small noncoding RNAs that play diverse roles in normal and disease biology, and they generally operate through the post-transcriptional regulation of mRNA targets. We have previously identified cellular miRNAs that have antiviral activity against a broad range of herpesvirus infections, and here we extend the antiviral profile of a number of these miRNAs against influenza and respiratory syncytial virus. From these screening experiments, we identified broad-spectrum antiviral miRNAs that caused >75% viral suppression in all strains tested, and we examined their mechanism of action using reverse-phase protein array analysis. Targets of lead candidates, miR-124, miR-24, and miR-744, were identified within the p38 mitogen-activated protein kinase (MAPK) signaling pathway, and this work identified MAPK-activated protein kinase 2 as a broad-spectrum antiviral target required for both influenza and respiratory syncytial virus (RSV) infection.

Targeted Gene Editing of Glia Maturation Factor in Microglia: a Novel Alzheimer’s Disease Therapeutic Target

“…Recently, deficiency of neuronal p38alpha MAPK has been shown to attenuate amyloid pathology in AD mouse and cellular models [75]. Interestingly, mir-744, mir-124a and mir-24 mimics have been shown to suppress both p38 MAPK expression and activation [76]. Similarly, LPS treatment of the hippocampal HT-22 cells has been shown to downregulate mir-132 expression which in turn upregulates the expression of the target gene TRAF6 causing activation of the NFκB and MEK/ERK pathways [77].…”

MicroRNA Involvement in Signaling Pathways During Viral Infection

“…In this case, the mechanism seems to be similar to the one described in the case of miR-21 and CVB3, with decreased levels of phosphorylated p38 showing a reduced activation of this component. Furthermore, a significant reduction in the expression of p38 MAPK has also been demonstrated through decreased levels of proteins (McCaskill et al, 2017).…”

“…In this case, the miRNAs involved are miR-24, miR-124, and miR-744. However, besides the decrease in the activation of p38 component due to a lack of phosphorylation, there has also been demonstrated a reduction in the overall levels of the same member (McCaskill et al, 2017;He et al, 2019).…”

The Two Sides of the Same Coin—Influenza Virus and Intracellular Signal Transduction

“…By using chemical inhibitors as well as knockout cell lines, it was shown that MAPK p38-dependent phosphorylation of TRIM28 facilitates a functional switch leading to increased cytokine levels in cells infected with highly pathogenic viruses (Krischuns et al 2018). Besides its role in the induction of pro-inflammatory and antiviral cytokines, there have been reports of a virus-supportive function of MAPK p38 observed after inhibition of the pathway with different p38 inhibitors (Marchant et al 2010;Choi et al 2016;McCaskill et al 2017). Deeper investigation provided evidence of a potential role of p38 in Toll-like receptor 4-mediated virus internalization, which is based on p38catalyzed phosphorylation of early endosome antigen 1 (EEA1), which increases endocytotic activity.…”