DefensePredictor: A Machine Learning Model to Discover Novel Prokaryotic Immune Systems

Anti-phage defense systems protect bacteria from viruses. Studying defense systems has begun to reveal the evolutionary roots of eukaryotic innate immunity and produced important biotechnologies such as CRISPR-Cas9. Dozens of new systems have been discovered by looking for systems that co-localize in genomes, but this approach cannot identify systems outside defense islands. Here, we present DefensePredictor, a machine-learning model that leverages embeddings from a protein language model to classify proteins as defensive. We applied DefensePredictor to 69 diverse E. coli strains and validated 45 previously unknown systems, with >750 additional unique proteins receiving high confidence predictions. Our model, provided as open-source software, will help comprehensively map the anti-phage defense landscape of bacteria, further reveal connections between prokaryotic and eukaryotic immunity, and accelerate biotechnology development.