Pathogenicity and virulence of <i>Streptococcus suis</i> serotype 2: Emerging insights and persistent knowledge gaps

serotype 2 is a major zoonotic pathogen causing meningitis, septicemia, streptococcal toxic shock-like syndrome (STSLS) in swine and humans. This review synthesizes discoveries over the past decade, organized around the infection progression, colonization, bloodstream survival, immune evasion, blood-brain barrier disruption, excessive inflammation culminating in STSLS. We dissect regulatory architecture including two-component systems, Ser/Thr kinase STK, small RNAs, toxin-antitoxin modules, and stringent response. We analyze functional effectors enabling niche adaptation, including capsule, pili, metabolic enzymes, metal acquisition systems, complement evasins, and suilysin. A dedicated section addresses critical controversies, including roles of CovR, phenotypes of SsnA and IdeS_suis, and dual functions of Fpr2. We evaluate translational implications, highlighting vaccine candidates and antivirulence targets. Knowledge gaps remain, including unknown targets of regulatory systems, unexplored post-translational modifications, discrepancies between mouse models and natural porcine infections. Future studies must prioritize natural-route infection models in pigs and systems-level approaches to translate discoveries into interventions.