5'-Triphosphate-short interfering RNA: potent inhibition of influenza A virus infection by gene silencing and RIG-I activation.
Limited protection of current vaccines and antiviral drugs against influenza A virus infection underscores the urgent need for development of novel anti-influenza virus interventions. While short interfering RNA (siRNA) has been shown to be able to inhibit influenza virus infection in a gene-specific manner, activation of the retinoic acid-inducible gene I protein (RIG-I) pathway has an antiviral effect in a non-gene-specific mode. In this study, we designed and tested the anti-influenza virus effect of a short double-stranded RNA, designated 3p-mNP1496-siRNA, that possesses dual functions: an siRNA-targeting influenza NP gene and an agonist for RIG-I activation. This double-stranded siRNA possesses a triphosphate group at the 5' end of the sense strand and is blunt ended. Our study showed that 3p-mNP1496-siRNA could potently inhibit influenza A virus infection both in cell culture and in mice. The strong inhibition effect was attributed to its siRNA function as well as its ability to activate the RIG-I pathway. To the best of our knowledge, this is the first report that the combination of siRNA and RIG-I pathway activation can synergistically inhibit influenza A virus infection. The development of such dual functional RNA molecules will greatly contribute to the arsenal of tools to combat not only influenza viruses but also other important viral pathogens.
Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Li
L
Lin
Qiang
Q
Liu
Nathalie
N
Berube
Susan
S
Detmer
Yan
Y
Zhou
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002645:Chickens; D002522:Chlorocebus aethiops; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D005260:Female; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D009980:Influenza A virus / Q000235:genetics*; D007251:Influenza, Human / Q000235:genetics* / Q000821:virology*; D016899:Interferon-beta / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010710:Phosphates / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000378:metabolism*; D011971:Receptors, Immunologic; D014709:Vero Cells
D010710:Phosphates; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D016899:Interferon-beta; C452820:RIGI protein, human; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases