Evolutionary immunology: using insect models to unravel STING-dependent conserved and innovative antiviral strategies (Evo-immuno)

As we have seen with the emergence of viral pathogens like Ebola, ZIKA and SARS-CoV2, our societies are, and will continue to be, confronted to unknown and perilous viruses. To prepare for this, we propose to explore the diversity of antiviral genes in animals. Important signaling nodes have been conserved throughout evolution and regulate expression of antiviral genes that evolve dynamically in response to viral pressure. Because this occurs in parallel between different lineages, each animal has a unique arsenal of antiviral genes, with a core of conserved genes, but also taxon-specific genes, which represent an unexplored resource of potentially unique antiviral mechanisms. Insects, the largest group of animals, present high potential for such project but lack of information on the viruses infecting most of them prevented broad investigation up to now. Our discovery that the cyclic dinucleotide (CDN) cGAMP triggers a strong STING- and NF-B-dependent antiviral protection in drosophila, provides for the first time a handle to access the repertoire of induced antiviral genes in insects. We will exploit the assets of the drosophila model to address the function of cGAS-like receptors and the CDNs they produce. We will use RNA sequencing of cGAMP-stimulated insects and evolution-guided paradigms to identify among the STING-regulated genes candidates for functional antiviral screens in insect and human cells. Hits will be characterized to understand their mode of action. As proof of principle, we will study the function of Nazo, a fast-evolving STING-regulated gene duplicate in drosophila also strongly upregulated by interferons in bats. Overall, this project will provide a unique evolutionary perspective on the STING pathway and will lay the foundations for exploitation of rapidly increasing genomic data to document original antiviral strategies, with the long-term goal of inspiring innovative therapeutic approaches against viral infections.