Fish pathogen armor: A review of antiphage defense systems in bacterial fish pathogens

Bacterial diseases remain a major bottleneck to sustainable aquaculture, and interest in bacteriophage (phage) therapy has surged accordingly. However, the efficacy and durability of phage interventions are constrained by the range of chromosomally encoded antiphage defense systems in fish-pathogenic bacteria. Here, we survey publicly available genomes to establish an aquaculture-centric landscape of these defenses and their implications for therapeutic design. Across 272 genomes representing 35 fish-pathogenic species, we identified 1,174 antiphage defense systems spanning 304 distinct defense types (e.g., CRISPR-Cas, restriction-modification, DISARM, BREX, CBASS). Core systems (restriction–modification and CRISPR-Cas) are widespread, while emerging systems show patchy, lineage-specific distributions. Genomic context analysis reveals frequent clustering into defense “islands” and recurrent co-occurrence patterns, suggesting modular acquisition and potential redundancy. To translate these findings, we compile a curated crosswalk of defense types versus known phage countermeasures (anti-CRISPRs, DNA mimic proteins, anti-CBASS factors, and others) and critically appraise evidence for phage therapy from laboratory to farm settings in aquaculture species. Together, these results (i) delineate defense repertoires most likely to impede single-phage treatments, (ii) highlight taxa where cocktail rotation or engineered anti-defense traits may be necessary, and (iii) provide a practical decision framework for candidate selection, monitoring, and stewardship. This study delivers a consolidated resource and actionable guidance for rational phage development and deployment against fish-pathogenic bacteria, supporting more resilient, evidence-based disease control in aquaculture.