2'3'-cGAMP triggers a STING and NF-κB dependent broad antiviral response in Drosophila

Abstract

We recently reported that an orthologue of STING regulates infection by picorna-like viruses in drosophila. In mammals, STING is activated by the cyclic dinucleotide 23-cGAMP produced by cGAS, which acts as a receptor for cytosolic DNA. Here, we show that injection of flies with 23-cGAMP can induce expression of dSTING-regulated genes. Co-injection of 23-cGAMP with a panel of RNA or DNA viruses results in significant reduction of viral replication. This 23-cGAMP-mediated protection is still observed in flies mutant for the genes Atg7 and AGO2, which encode key components of the autophagy and small interfering RNA pathways, respectively. By contrast, it is abrogated in flies mutant for the NF-{kappa}B transcription factor Relish. Analysis of the transcriptome of 23-cGAMP injected flies reveals a complex pattern of response, with early and late induced genes. Our results reveal that dSTING regulates an NF-{kappa}B-dependent antiviral program, which predates the emergence of Interferon Regulatory Factors and interferons in vertebrates.