Suilysin Stimulates the Release of Heparin Binding Protein from Neutrophils and Increases Vascular Permeability in Mice

Abstract

Most of the deaths that occurred during two large outbreaks of Streptococcus suis infections in 1998 and 2005 in China were caused by streptococcal toxic shock syndrome (STSS), which is characterized by increased vascular permeability. Heparin-binding protein (HBP) is thought to mediate the vascular leakage. The purpose of this study was to investigate the detailed mechanism underlying the release of HBP and the vascular leakage induced by S. suis. Significantly higher serum levels of HBP were detected in Chinese patients with STSS than in patients with meningitis or healthy controls. Suilysin (SLY) is an exotoxin secreted by the highly virulent strain 05ZYH33, and it stimulated the release of HBP from the polymorphonuclear neutrophils and mediated vascular leakage in mice. The release of HBP induced by SLY was caused by a calcium influx-dependent degranulation. Analyses using a pharmacological approach revealed that the release of HBP induced by SLY was related to Toll-like receptor 4, p38 mitogen-activated protein kinase, and the 1-phosphatidylinositol 3-kinase pathway. It was also dependent on a G protein-coupled seven-membrane spanning receptor. The results of this study provide new insights into the vascular leakage in STSS associated with non-Group A streptococci, which could lead to the discovery of potential therapeutic targets for STSS associated with S. suis.

Heparin‐binding protein: a key player in the pathophysiology of organ dysfunction in sepsis

“…These chemotactic factors such as IL‐8 activate neutrophils and lead to HBP release . Bacterial proteins can also directly activate neutrophils and release HBP . These proteins include M1 protein from Streptococcus pyogenes , suilysin from Streptococcus suis and phenol‐soluble modulin alpha4 from Staphylococcus aureus .…”

“…Bacterial proteins can also directly activate neutrophils and release HBP . These proteins include M1 protein from Streptococcus pyogenes , suilysin from Streptococcus suis and phenol‐soluble modulin alpha4 from Staphylococcus aureus . Neutrophils are also activated upon contact with cellular adhesion molecules on the endothelial cell surface , and subsequent HBP release leads to increased endothelial permeability, facilitating neutrophil extravasation to the site of infection .…”

“…As stated above, a specific molecular mechanism for the triggering of HBP release by a bacterium has only been shown for Gram‐positive bacteria . Whether or not a similar mechanism exists for Gram‐negative bacteria is unknown although endotoxaemia has been shown to induce HBP release in pigs .…”

A Promising Candidate: Heparin-Binding Protein Steps onto the Stage of Sepsis Prediction

“…Phenol-soluble modulin α4 (PSMα4) derived from Staphylococcus aureus binds to formyl peptide receptor 2 (FPR2) on the surface of PMNs to active PI3K signaling pathways to induce HBP release [8]. LTB4 and suilysin derived from Streptococcus suis both similarly trigger PI3K pathways through their interactions with the BLT1 and TLR4 receptors, respectively [9,37]. Additionally, G-protein-coupled receptors and p38 MAPK are also involved in the release of 2…”

“…Initially, this protein gained attention due to its antimicrobial properties [6], and later, it was determined that HBP acted as a multifunctional mediator in infection and inflammation. HBP is prefabricated in PMNs [7] and released rapidly after stimuli by various bacterial structures [8][9][10][11], cytokines, inflammation factors, and chemotactic factors [12]. When released, HBP can exert significant subsequent effects on the immune system.…”