AbstractBackgroundMulticellular animals and bacteria frequently engage in predator-prey and host-pathogen interactions, such as the well-studied relationship betweenPseudomonas aeruginosaand the nematodeCaenorhabditis elegans. This study investigates the genomic and genetic basis of bacterial-driven variability inP. aeruginosavirulence towardsC. elegansto provide evolutionary insights into host-pathogen relationships.ResultsNatural isolates ofP. aeruginosathat exhibit diverse genomes display a broad range of virulence towardsC. elegans. Using gene association and genetic analysis, we identify accessory genome elements that correlate with virulence, including both known and novel virulence determinants. Among the novel genes, we find a viral-like mobile element, thetegblock, that impairs virulence and whose acquisition is restricted by CRISPR-Cas systems. Further genetic and genomic evidence suggests that spacer-targeted elements preferentially associate with lower virulence while the presence of CRISPR-Cas associates with higher virulence.ConclusionsOur analysis demonstrates substantial strain variation inP. aeruginosavirulence, mediated by specific accessory genome elements that promote increased or decreased virulence. We exemplify that viral-like accessory genome elements that decrease virulence can be restricted by bacterial CRISPR-Cas immune defense systems, and suggest a positive, albeit indirect, role for host CRISPR-Cas systems in virulence maintenance.