A minimal RNA ligand for potent RIG-I activation in living mice

By Melissa M. Linehan, T. Dickey, E. Molinari, Megan E. Fitzgerald, O. Potapova, A. Iwasaki, Anna Marie Pyle. 2017

104 citations recorded by the source corpus.

Short stem-loop RNAs activate RIG-I in mice, activating the innate immune system via specific patterns of gene expression. 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.

Subfields: Immunology, Molecular Biology, Oncology

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In Immunology

1. Wenshuai Wang
2. Anna Marie Pyle

In Molecular Biology

1. Wenshuai Wang
2. C. S. Sullivan
3. Anna Marie Pyle

In Oncology

1. Wenshuai Wang
2. Anna Marie Pyle

Citations in the corpus

• The RIG-I receptor adopts two different conformations for distinguishing host from viral RNA ligands (2022, positive): “Although these dsRNAs can be of any length, short dsRNAs (10–20 base pairs), such as those found in a genomic viral RNA panhandle, are particularly potent RIG-I agonists (Kohlway et al., 2013; Linehan et al., 2018; Liu et al., 2015).”
• DUSP11-mediated control of 5′-triphosphate RNA regulates RIG-I sensitivity (2020, background): “However, overt differences inWT orM51RVSV replication were not observed in the HEK293 background, likely due to the highly attenuated antiviral response of HEK293 cells (Supplemental Fig. S3E; Reynolds 2006; Linehan et al. 2018; Thomsen et al. 2019).”