A Minimal RNA Ligand for Potent RIG-I Activation in Living Mice

Sci Adv. 2018 Feb 21;4(2):e1701854. doi: 10.1126/sciadv.1701854. eCollection 2018 Feb.

Abstract

We have developed highly potent synthetic activators of the vertebrate immune system that specifically target the RIG-I receptor. When introduced into mice, a family of short, triphosphorylated stem-loop RNAs (SLRs) induces a potent interferon response and the activation of specific genes essential for antiviral defense. Using RNA sequencing, we provide the first in vivo genome-wide view of the expression networks that are initiated upon RIG-I activation. We observe that SLRs specifically induce type I interferons, subsets of interferon-stimulated genes (ISGs), and cellular remodeling factors. By contrast, polyinosinic:polycytidylic acid [poly(I:C)], which binds and activates multiple RNA sensors, induces type III interferons and several unique ISGs. The short length (10 to 14 base pairs) and robust function of SLRs in mice demonstrate that RIG-I forms active signaling complexes without oligomerizing on RNA. These findings demonstrate that SLRs are potent therapeutic and investigative tools for targeted modulation of the innate immune system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • DEAD Box Protein 58 / metabolism*
  • Gene Expression Regulation / drug effects
  • HEK293 Cells
  • Humans
  • Interferons / pharmacology
  • Ligands
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nucleic Acid Conformation
  • Phosphorylation / drug effects
  • Poly I-C / pharmacology
  • RNA / chemistry
  • RNA / metabolism*

Substances

  • Ligands
  • RNA
  • Interferons
  • DDX58 protein, human
  • Ddx58 protein, mouse
  • DEAD Box Protein 58
  • Poly I-C