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

Introduction

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 with unknown and perilous viruses. To prepare for this, we propose to explore the diversity of antiviral genes in animals.

Antiviral Gene Diversity

Important signaling nodes have been conserved throughout evolution and regulate the 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, which includes:

• A core of conserved genes
• Taxon-specific genes, representing an unexplored resource of potentially unique antiviral mechanisms

Focus on Insects

Insects, the largest group of animals, present high potential for such a project. However, the lack of information on the viruses infecting most of them has prevented broad investigation up to now.

Discovery of cGAMP

Our discovery that the cyclic dinucleotide (CDN) cGAMP triggers a strong STING- and NF-κB-dependent antiviral protection in Drosophila provides, for the first time, a handle to access the repertoire of induced antiviral genes in insects.

Project Objectives

We will exploit the assets of the Drosophila model to address the function of cGAS-like receptors and the CDNs they produce. The main objectives include:

1. Using RNA sequencing of cGAMP-stimulated insects
2. Applying evolution-guided paradigms to identify among the STING-regulated genes candidates for functional antiviral screens in insect and human cells
3. Characterizing hits to understand their mode of action

Proof of Principle

As proof of principle, we will study the function of Nazo, a fast-evolving STING-regulated gene duplicate in Drosophila that is also strongly upregulated by interferons in bats.

Conclusion

Overall, this project will provide a unique evolutionary perspective on the STING pathway and will lay the foundations for the exploitation of rapidly increasing genomic data to document original antiviral strategies, with the long-term goal of inspiring innovative therapeutic approaches against viral infections.