Mechanisms and evolution of innate immune signalling activation across species

Only certain species act as pathogen vectors or reservoirs for diseases such as COVID-19, malaria, or tuberculosis. Variability in disease outcome is partly driven by differential activation of the immune system after otherwise identical infections, particularly true for inflammatory diseases such as Influenza and COVID-19. The inflammatory response is driven first by activation of innate immunity: an evolutionarily conserved defence system built upon recognition, signalling, and effector molecules. Genes involved in the innate immune response are some of the most rapidly evolving in the genome. Previous analyses have highlighted recognition and signalling proteins in particular as having very high rates of adaptive evolution. However, few studies have examined innate immune induction across related species, and little effort has been made to understand how molecular evolution in conserved immune pathway genes might drive differences in immune induction across species. My research has shown related fly species given identical infections can differ markedly in their induced immune response. Here, I will take a comparative approach to systematically characterize immune induction patterns in diverse species. Differences in immune induction should rely on either i) alternate immune signalling epistasis/cross-talk, or ii) specificity encoded via gene duplication, allowing evolution of novel pathway connections. I will assess gene expression, copy number variation, sequence evolution, and signalling epistasis, to understand how these variables produce differences in immune activation. I will then tie immune evolution to differences in the induced response to infection. This will reveal the mechanisms underlying differences in immune activation across species. Major global threats such as COVID-19, malaria, or tuberculosis, each induce common immune pathways shared by all animals. This proposal will therefore greatly improve our ability to predict interactions between novel hosts and pathogens, and understand innate immune factors affecting disease severity.