Suilysin of <i>Streptococcus suis</i> Serotype 2 Drives Astrocyte Pyroptosis via Activation of the ROS/NLRP3/Caspase-1/GSDMD Pathway

Emerging evidence indicates that pyroptosis contributes to neuroinflammation and central nervous system (CNS) injuries. However, its role in Streptococcus suis ( S. suis )-induced brain damage remains unclear. Here, we demonstrate that S. suis strain P1/7 infection triggers pyroptosis in astrocytes, specifically characterized by activating NLRP3/caspase-1/GSDMD axis. Suilysin (SLY), a key virulence factor of S. suis, dose- and time-dependently induced pyroptosis in U251 cells. Notably, genetic ablation of NLRP3 or GSDMD significantly attenuated SLY-induced pyroptosis, and caspase-1 inhibition similarly suppressed this process. Furthermore, SLY promoted reactive oxygen species (ROS) production, and scavenging ROS inhibited NLRP3/caspase-1/GSDMD activation and pyroptosis. Consistently, in a murine infection model, S. suis P1/7 induced astrocyte pyroptosis in brain tissues, while its sly deleted mutant (P1/7-Δ sly ) significantly reduced this effect. These findings reveal that SLY mediates pyroptosis in astrocytes via the ROS/NLRP3/caspase-1/GSDMD pathway, highlighting its critical role in S. suis -induced neuropathogenesis.