Conservation of defense and anti-defense mechanisms across the tree of life

forthcoming

Across the tree of life, genetic conflicts between hosts and pathogens have fueled the diversification of intracellular defenses that collectively define innate immunity. While prokaryotic and eukaryotic immunity have long been considered distinct, the recent discoveries of multiple defense systems protecting bacteria against viruses called phages have profoundly challenged this paradigm. In particular, some components of eukaryotic innate immunity were shown to have a deep evolutionary origin in bacterial defenses. The existence of ancient immune components suggests that phage-bacteria interactions can illuminate the genetic conflicts between hosts and pathogens across the tree of life, which I propose to explore through two angles. Firstly, I propose to discover novel players of innate immunity based on bacterial defenses. A bioinformatic pipeline will systematically predict protein domains that trigger immune cell death in bacterial defenses and are conserved in eukaryotes. These effectors will be biochemically characterized in bacteria and beyond to unveil novel immune strategies disseminated across the tree of life. We will then exploit this evolutionary conservation to engineer novel immune proteins in human cells based on effectors found in other kingdoms of life. Secondly, I hypothesize that phages and eukaryotic viruses in turn evolved similar strategies to evade immunity. We aim to discover new anti-defenses in phages and to translate them to the world of eukaryotic viruses. To do so, we will implement high-throughput screens to test the anti-defense activity of thousands of small phage genes. We will also conduct structural homology searches to reveal anti-defense mechanisms shared between phages and eukaryotic viruses and characterize them experimentally. Altogether, this project will reveal novel molecular mechanisms of defense and anti-defense in bacteria and beyond, shedding light on the principles of host-pathogen interactions across the biosphere.