The cholesterol-dependent cytolysin promotes Streptococcus systemic spread and induces arachidonic acid accumulation-mediated lethality in a murine intraperitoneal infection model.

Streptococcal peritonitis is associated with a high mortality risk and sometimes accompanied by streptococcal toxic shock-like syndrome (STSLS). Here, we used a murine intraperitoneal model of Streptococcus suis serotype 2 (SS2) infection and applied bacterial lineage tracing to investigate the pathogen's population dynamics during streptococcal intraperitoneal infection. We found that the cholesterol-dependent cytolysin suilysin (SLY) was essential for acute lethality and facilitated bacterial systemic spread by mitigating infection bottlenecks and enabling vascular leakage in the peritoneal cavity. SLY induced marked accumulation of arachidonic acid (AA) in the peritoneal cavity. Although inhibition of AA synthesis alone did not prevent mortality, it widened the therapeutic window of antibiotic treatment, enhancing their efficacy and capacity to reduce lethality. These findings identify SLY as a critical virulence determinant linking inflammation-associated metabolic alterations, disruption of vascular integrity, and mortality and highlight AA metabolism as a promising adjunctive therapeutic target for acute SS2 intraperitoneal infection.