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

IF 4.5 2区医学 Q2 CHEMISTRY, MEDICINAL

ACS Infectious Diseases Pub Date : 2026-07-10 Epub Date: 2026-06-26 DOI:10.1021/acsinfecdis.6c00307

Ruicheng Yang, Lang Tian, Jundan Wang, Wenquan Ouyang, Huanchun Chen and Xiangru Wang*,

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引用次数: 0

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.

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猪链球菌血清2型溶素通过激活ROS/NLRP3/Caspase-1/GSDMD通路驱动星形胶质细胞凋亡

新出现的证据表明，焦亡有助于神经炎症和中枢神经系统（CNS）损伤。然而，其在猪链球菌（S. suis）引起的脑损伤中的作用尚不清楚。在这里，我们证明猪链球菌P1/7感染会触发星形胶质细胞的焦亡，具体特征是激活NLRP3/caspase-1/GSDMD轴。Suilysin （SLY）是猪链球菌的关键毒力因子，剂量和时间依赖性地诱导U251细胞热亡。值得注意的是，NLRP3或GSDMD的基因消融显著减轻了sly诱导的焦亡，caspase-1的抑制同样抑制了这一过程。此外，SLY促进活性氧（ROS）的产生，清除ROS可抑制NLRP3/caspase-1/GSDMD的激活和焦亡。与此一致的是，在小鼠感染模型中，猪链球菌P1/7诱导脑组织星形胶质细胞凋亡，而它的隐性缺失突变体P1/7-Δsly显著降低了这种作用。这些发现表明，SLY通过ROS/NLRP3/caspase-1/GSDMD通路介导星形胶质细胞的焦亡，突出了其在葡萄球菌诱导的神经发病机制中的关键作用。

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来源期刊

ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES

CiteScore

9.70

自引率

3.80%

发文量

213

期刊介绍： ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.