<b><i>Streptococcus suis</i></b><b> </b><b>s</b><b>erotype</b><b> 5</b><b>: emerging </b><b>zoonotic </b><b>threat</b><b> with </b><b>distinct</b><b> genomic heterogeneity</b>

<i>Streptococcus suis</i> is a significant pig pathogen and an emerging zoonotic agent. Serotype 5 is becoming an increasing concern among pigs and humans with <i>S. suis</i> 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 clustered into four groups: epidemic (E)(n=1), highly virulent plus (HV+)(n=4), HV(n=11), and virulent (V)(n=16). Virulence levels progressively decreased from the E group to HV+, HV, and V groups. The E, HV+, and HV strains induced significantly lethal infectionin mice during the early phase of infection. The lethal infection induced by E 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 E 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 strategiesfor <i>S. suis</i> serotype 5 infections was provided.