The RNA Receptor RIG-I Binding Synthetic Oligodeoxynucleotide Promotes Pneumonia Survival

Authors

Yongxing Wang
Vikram V Kulkarni
Jezreel PantaleónGarcía
Michael K Longmire
Mathilde Lethier
Stephen Cusack
Scott E Evans

Publication Date

11-8-2024

Journal

JCI Insight

Abstract

Pneumonia is a worldwide threat to public health, demanding novel preventative and therapeutic strategies. The lung epithelium is a critical environmental interface that functions as a physical barrier to pathogen invasion while also actively sensing and responding to pathogens. We have reported that stimulating lung epithelial cells with a combination therapeutic consisting of a diacylated lipopeptide and a synthetic CpG oligodeoxynucleotide (ODN) induces synergistic pneumonia protection against a wide range of pathogens. We report here that mice deficient in TLR9, the previously described receptor for ODN, still displayed partial ODN-induced protection. This prompted us to seek an alternate ODN receptor, and we discovered by mass spectroscopy that the RNA sensor RIG-I could also bind DNA-like ODN. ODN binding by RIG-I resulted in MAVS-dependent pneumonia-protective signaling events. While RIG-I is essential to native defenses against viral infections, we report that therapeutic RIG-I activation with ODN promoted pathogen killing and host survival following both viral and bacterial challenges. These data indicate that maximal ODN-induced pneumonia protection requires activation of both the TLR9/MyD88 and RIG-I/MAVS signaling pathways. These findings not only identify what we believe to be a novel pattern recognition receptor for DNA-like molecules, but reveal a potential therapeutic strategy to protect susceptible individuals against lethal pneumonias during periods of peak vulnerability.

Keywords

Animals, Mice, Oligodeoxyribonucleotides, DEAD Box Protein 58, Toll-Like Receptor 9, Signal Transduction, Pneumonia, Mice, Knockout, Mice, Inbred C57BL, Adaptor Proteins, Signal Transducing, Lung, Myeloid Differentiation Factor 88, Female, Male, Cell biology, Immunology, Bacterial infections, Influenza, Innate immunity

DOI

10.1172/jci.insight.180584

PMID

39352770

PMCID

PMC11601584

PubMedCentral® Posted Date

11-8-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes