SHAOLONG CHEN¹, WENLONG XIE¹, HUANG JIANG¹, YUAN YUAN¹, YONGQIANG JIANG<sup>1

1</sup>State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China

Abstract
Most deaths occurred during the 2 large outbreaks of Streptococcus suis infection in 1998 and 2005 in China were caused by streptococcal toxic shock syndrome characterized by an increased vascular permeability. Heparin binding protein is thought to mediate vascular leakage. The purpose of this study is to investigate the molecular mechanism underlying the HBP release and vascular leakage induced by S. suis. Significantly higher serum HBP levels were detected in Chinese patients with STSS. Then suilysin, an exotoxin secreted by highly virulent strain 05ZYH33, was identified to stimulate HBP release from polymorphonuclear neutrophils and mediate vascular leakage in mice. SLY induced HBP release was caused by calcium influx-dependent degranulation. Analyses using pharmacological approach revealed that SLY interacted with TLR4 to activate p38 MAPK pathway and up-regulated the gene expression of 5-lipoxygenase to secret leukotriene B4, which then activated PI3K pathway through G protein-coupled seven-membrane spanning receptor and induced HBP release from PMNs. The 5-LO inhibitor Zileuton significantly reduced SLY-induced HBP release and vascular leakage in mice, further supporting that 5-LO is involved in SLY-regulated signaling pathways. These findings might lead to the discovery of potential therapeutic targets for S. suis-associated STSS.

Keywords: 5-lipoxygenase, Heparin binding protein, Streptococcus suis-associated streptococcal toxic shock syndrome, suilysin, vascular permeability.