Genomic Insights into the Pathogenicity of Hypervirulent Aeromonas hydrophila Strain D4 Isolated from Diseased Blunt Snout Bream with the Epidemic Sequence Type 251 Clones

<i>Aeromonas hydrophila</i> ST251 is a crucial pathogen responsible for the outbreaks of Motile <i>Aeromonas</i> Septicemia (MAS) in global aquaculture. To elucidate the genetic basis underlying its hypervirulence, we investigated strain D4, an ST251 isolate recovered from diseased blunt snout bream. Phenotypic assays revealed that, compared to the environmental strain ATCC 7966^T, D4 exhibited enhanced motility, hemolytic activity, and protease production. Average nucleotide identity (ANI) analysis demonstrated that D4 clustered within a distinct ST251 clade, with ANI values ≥ 99.74%. Comparative genomic analysis of D4, nine additional ST251 strains, and ATCC 7966^T identified multiple unique genomic islands in ST251 strains, including pathways for <i>myo</i>-inositol and L-fucose utilization and a pseudaminic acid biosynthesis gene cluster. These genetic elements are associated with nutrient acquisition and flagellar assembly, potentially enhancing colonization and environmental adaptability. In addition, distinct plasmids and prophages in ST251 strains may contribute to host adaptation and virulence by regulating stress responses and virulence-associated genes. These findings offer new insights into the molecular mechanisms driving the pathogenicity and adaptability of hypervirulent <i>A. hydrophila</i> ST251 strains.