Abstract

Highlights•Bacterial homologs of eukaryotic innate immunity genes examined in P. aeruginosa•Over 400 eukaryotic-like bacterial antiviral candidates were identified•Six eukaryotic-like phage defense systems validated to have strong anti-phage activity•Findings underscore the shared evolutionary roots of viral defenses across the domainsSummaryProkaryotes have evolved a multitude of defense systems to protect against phage predation. Some of these resemble eukaryotic genes involved in antiviral responses. Here, we set out to systematically project the current knowledge of eukaryotic-like antiviral defense systems onto prokaryotic genomes, using Pseudomonas aeruginosa as a model organism. Searching for phage defense systems related to innate antiviral genes from vertebrates and plants, we uncovered over 450 candidates. We validated six of these phage defense systems, including factors preventing viral attachment, R-loop-acting enzymes, the inflammasome, ubiquitin pathway, and pathogen recognition signaling. Collectively, these defense systems support the concept of deep evolutionary links and shared antiviral mechanisms between prokaryotes and eukaryotes.Graphical abstract