Functional evolution of the cell autonomous innate immunity in mammals

Objective

Cell-autonomous innate immunity is the first line of defense against pathogens and is crucial in infections, viral cross-species transmissions and autoimmunity. In mammals, it is notably composed of proteins from the interferon pathway inhibiting viruses within infected cells. In turn, viruses evade or antagonize immunity, leading to virus-host evolutionary arms-races. Beyond classic adaptation by site-specific positive selection, we discovered cases of gene duplications with divergence in gene expression and sequence, including by protein domain rearrangements, that appear adaptive in Myotis bats. I thus hypothesize that recurrent gene duplications and domain rearrangements represent overlooked biological principles in the diversification of mammalian innate immunity, enabling hosts to keep up against rapidly evolving viruses. I further hypothesize that we can use these evolutionary cues to distinctively discover novel innate immune genes. FUNEVO bridges the fields of evolutionary biology and antiviral innate immunology to decipher conceptual novelties on the evolutionary rules governing mammalian immunity. Aim 1 combines phylogenomics, with state-of-the-art CRISPR loss-of-function and homologs’ gain-of-function antiviral screens, in the Myotis cross-discipline model platform that we newly established, to discover immune innovations driving antiviral specificity. In Aim 2, we use recent breakthroughs in genomics and protein domain structure predictions to identify and quantify immune innovations during mammalian evolution. In Aim 3, through ancestral reconstructions combined with mechanistic characterization, we will understand how the identified gene duplications and domain rearrangements led to functional novelty. Overall, our evolution-guided approach will unveil novel antiviral genes that emerged in mammals, shedding lights on the evolutionary principles that were crucial to innate immune evolution and have the potential to inspire future disease therapy.