serotype 5: Emerging zoonotic threat with distinct genomic heterogeneity.

is a significant pig pathogen and an emerging zoonotic agent. Serotype 5 is becoming an increasing concern among pigs and humans with infection worldwide. This study investigated the population structure, phylogenetic relationship, genomic characteristics, and virulence of serotype 5 population, analyzing 89 isolates, including eight from human cases. The results revealed significant genomic heterogeneity and diverse virulence levels within serotype 5 population. Phylogenetic analysis identified two distinct lineages with notable differences in evolution and genomic traits. Thirty-two representative serotype 5 strains were clustered into four groups: ultra-highly virulent (UV) ( = 1), highly virulent plus (HV) ( = 4), HV ( = 11), and virulent (V) ( = 16). Virulence levels progressively decreased from the UV group to HV, HV, and V groups. The UV, HV, and HV strains induced significantly lethal infection in mice during the early phase of infection. The lethal infection induced by UV and HV strains was time-dependent but dose-independent. Ultra-high bacterial loads, excessive pro-inflammatory cytokines, and severe organ damage were responsible for the sudden death of mice infected with UV strain at the early phase of infection. The capacity to establish infection, induce excessive pro-inflammatory cytokine production, and elevate biomarkers associated with organ damage varied significantly among HV strains. The V strains demonstrated the capacity to induce delayed lethal infection. These findings emphasized the serious public health risk posed by serotype 5 strains. The valuable information for developing effective prevention and control strategies for serotype 5 infections was provided.