Abstract
Pathogen-associated molecular patterns, including cytoplasmic DNA and double-strand (ds)RNA trigger the induction of interferon (IFN) and antiviral states protecting cells and organisms from pathogens. Here we discovered that the transfection of human airway cell lines or non-transformed fibroblasts with 24mer dsRNA mimicking the cellular micro-RNA (miR)29b-1* gives strong anti-viral effects against human adenovirus type 5 (AdV-C5), influenza A virus X31 (H3N2), and SARS-CoV-2. These anti-viral effects required blunt-end complementary RNA strands and were not elicited by corresponding single-strand RNAs. dsRNA miR-29b-1* but not randomized miR-29b-1* mimics induced IFN-stimulated gene expression, and downregulated cell adhesion and cell cycle genes, as indicated by transcriptomics and IFN-I responsive Mx1-promoter activity assays. The inhibition of AdV-C5 infection with miR-29b-1* mimic depended on the IFN-alpha receptor 2 (IFNAR2) and the RNA-helicase retinoic acid-inducible gene I (RIG-I) but not cytoplasmic RNA sensors MDA5 and ZNFX1 or MyD88/TRIF adaptors. The antiviral effects of miR29b-1* were independent of a central AUAU-motif inducing dsRNA bending, as mimics with disrupted AUAU-motif were anti-viral in normal but not RIG-I knock-out (KO) or IFNAR2-KO cells. The screening of a library of scrambled short dsRNA sequences identified also anti-viral mimics functioning independently of RIG-I and IFNAR2, thus exemplifying the diverse anti-viral mechanisms of short blunt-end dsRNAs.
Trial registration: ClinicalTrials.gov NCT02735824 .
Keywords: DNA virus; RIG-I; RNA therapy; RNA virus; SARS-CoV-2; adenovirus; antiviral agents; influenza virus; interferon; short double-strand blunt-end RNA.
【저자키워드】 SARS-CoV-2, interferon, Influenza virus, Adenovirus, Antiviral agents, RIG-I, RNA virus, DNA virus, RNA therapy, short double-strand blunt-end RNA., 【초록키워드】 Gene Expression, Antiviral, Influenza, transcriptomics, Infection, influenza A virus, interferon, antiviral effects, Influenza virus, influenza A, RNAs, cell cycle, Antiviral effect, Anti-viral, RNA, Adenovirus, Randomized, DNA, pathogen, cells, MDA5, Antiviral agents, IFN-I, IFN, retinoic acid-inducible gene I, RIG-I, Pathogens, pathogen-associated molecular patterns, receptor, RNA virus, retinoic acid, mechanism, IFN-alpha, cellular, IFNAR2, dsRNA, DNA virus, complementary, independent of, Organisms, molecular patterns, sequence, H3N2, organism, human airway, library, cell line, transfection, cell cycle genes, knock-out, MYD88, fibroblast, Cell, independent, adaptors, dsRNAs, ZNFX1, indicated, assays, required, cytoplasmic, elicited, downregulated, mimicking, anti-viral effect, 【제목키워드】 RNA, Effect, Type,