ATP-driven detection of foreign proteins triggers diverse mechanisms of cellular defense and phage-mediated counter defense

PROJECT SUMMARY Viruses are generally considered to be agents of destruction that must be efficiently eliminated by the host for self-preservation. However, viruses are also the largest reservoir of genetic diversity on the planet, and viral infections (estimated 1023 infections per second) are a primary mechanism for delivering new genes to naïve hosts. Thus, viruses have a complex role in the process of evolution, being both a major source of disease and mortality, while simultaneously presenting the cellular community with new opportunities for genetic innovation. In bacteria, viruses (i.e., phages) are major purveyors of genes that confer virulence and antibiotic resistance, and thus play a major role in the evolution of bacterial pathogenesis. The long-term goal of our research is to understand the impact of phage defense systems on the evolution and ecology of human-associated microbial communities, while also identifying and prioritizing research aimed at understanding immune systems that are conserved across domains of life. Specifically, the work outlined in this proposal will determining the phylogenetic and functional diversity of ATP-driven immune systems in bacteria, and how these systems recognize diverse viral proteins. We use bioinformatics and phylogenetics to guide structural, biological, and biochemical experiments to determine how foreign proteins are recognized, how detection of antigenic proteins trigger the activation of diverse immune effectors that block viral infection, and how viruses escape protection by these systems. Results from this research will add fundamental new insights to our understanding of the mechanism of viral defense, help explain the origins and evolution of immune systems, and may lead to new mechanistic insights that can be creatively repurposed for applications in human health.