Investigating the Evolution of Drosophila STING-Dependent Antiviral Innate Immunity by Multispecies Comparison of 2′3′-cGAMP Responses

Abstract

Viruses represent a major threat for all animals, which defend themselves through induction of a large set of virus-stimulated genes that collectively control the infection. In vertebrates, these genes include interferons that play a critical role in the amplification of the response to infection. Virus- and interferon-stimulated genes include restriction factors targeting the different steps of the viral replication cycle, in addition to molecules associated with inflammation and adaptive immunity. Predictably, antiviral genes evolve dynamically in response to viral pressure. As a result, each animal has a unique arsenal of antiviral genes. Here, we exploit the capacity to experimentally activate the evolutionarily conserved STING signaling pathway by injection of the cyclic dinucleotide 2′3′-cGAMP into flies to define the repertoire of STING-regulated genes in ten Drosophila species, spanning 50 million years of evolution. Our data reveal a set of conserved STING-regulated factors, including STING itself, a cGAS-like receptor, the restriction factor pastrel, and the antiviral protein Vago, but also two key components of the antiviral RNA interference pathway, Dicer-2 and Argonaute2. In addition, we identify unknown species- or lineage-specific genes that have not been previously associated with resistance to viruses. Our data provide insight on the core antiviral response in Drosophila flies and pave the way for the characterization of previously unknown antiviral effectors.