The origins and evolution of eukaryotic antibacterial defenses

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PROJECT SUMMARY Molecular mechanisms of innate immunity are constantly changing as organisms evolve to defend against the threats of newly emerged pathogens. As a consequence, our innate immune pathways are a patchwork of both ancient and recently evolved proteins. How did mechanisms of innate immunity arise, and how have these pathways adapted to integrate new defenses? The answers to these questions are important because these dynamics have shaped the functions of modern-day immunity, determining how hosts are protected from infectious diseases. Moreover, because immune pathways are evolutionarily flexible, they can serve as an excellent model for how cellular signaling networks assemble and diversify more broadly. We focus on the evolution of cell-autonomous immunity, which provides critical protections within infected cells. Aspects of cell-autonomous immunity are found across eukaryotes, including in unicellular phagocytic organisms that interact with bacteria in natural environments. To understand how ancient immune proteins have assembled into modern mammalian pathways, we use diverse eukaryotes at ideal phylogenetic positions to uncover the origins and evolution of innate immunity. We use the highly tractable Dictyostelium system to discover and characterize antibacterial defenses in amoebae, while leveraging additional eukaryotes to understand how immune proteins and pathways have evolved. Our experiments integrate molecular, biochemical, genetic, cellular, evolutionary, and genomic approaches to reveal genes functionally important for defending against bacterial infections in diverse organisms. Because cell-autonomous defenses are easier to observe and study in haploid, unicellular species, these experiments promise to uncover new mechanisms of cell-autonomous immunity. Some of these mechanisms may be deeply conserved with immune defenses in animals, allowing us to reconstruct how these immune pathways arise and change. Other immune mechanisms in these diverged eukaryotes may represent novel evolutionary solutions to the problem of cellular defense, yielding both practical molecular tools such as new antimicrobials and novel paradigms of immunity.