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

  • ACS Infect Dis. 2026 Jul 10;12(7):2345-2357. doi: 10.1021/acsinfecdis.6c00307.
Ruicheng Yang  1  2  3 ,  Lang Tian  2  3 ,  Jundan Wang  2  3 ,  Wenquan Ouyang  2  3 ,  Huanchun Chen  2  3  4  5 ,  Xiangru Wang  2  3  4  5
Affiliations
  • 1. School of Life Sciences, Jianghan University, Wuhan 430056, China.
  • 2. National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
  • 3. Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China.
  • 4. Engineering Research Center of Animal Biopharmaceuticals, The Ministry of Education of the People's Republic of China (MOE), Wuhan 430070, China.
  • 5. Frontiers Science Center for Animal Breeding and Sustainable Production, Huazhong Agricultural University, Wuhan 430070, China.
PMID: 42362498 DOI: 10.1021/acsinfecdis.6c00307
Abstract

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-Δsly) 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.

Keywords
NLRP3/caspase-1/GSDMD pathway; Streptococcus suis serotype 2; astrocytes; pyroptosis; suilysin.
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