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.
Highlights
Streptococcus suis has been recognized as an emerging zoonotic pathogen (Staats et al, 1997; Lun et al, 2007; Segura, 2009; Wertheim et al, 2009; Gottschalk et al, 2010)
A comparison of serum Heparinbinding protein (HBP) levels between patients with S. suis-associated streptococcal toxic shock syndrome (STSS) versus patients without STSS or healthy individuals revealed that the serum HBP levels in patients with STSS were significantly higher than those in patients with meningitis or healthy controls (46.61 ± 9.49 ng/mL vs. 11.52 ± 5.20 ng/mL or 1.84 ± 0.96 ng/mL, respectively; P = 0.0007, Figure 1), which suggested that HBP is released during the progression of STSS in patients infected with S. suis
Both the ELISA and Western blotting analyses demonstrated that the bacterial culture of the highly virulent S. suis strain 05ZYH33 significantly increased the release of HBP in the whole blood of healthy individuals (Figure 2A) and in purified polymorphonuclear neutrophils (PMNs) suspension (Figures 2B,C), whereas THB media without 05ZYH33 failed to induce the release of HBP in a whole blood sample or a PMN suspension
Summary
Streptococcus suis has been recognized as an emerging zoonotic pathogen (Staats et al, 1997; Lun et al, 2007; Segura, 2009; Wertheim et al, 2009; Gottschalk et al, 2010). Since the first human infection was identified in 1968 in Denmark (Perch et al, 1968), more than 400 cases of S. suis infection have been reported worldwide during the subsequent four decades (Lun et al, 2007). Most of these cases presented as meningitis, septicemia, endocarditis, arthritis, or pneumonia (Staats et al, 1997; Lun et al, 2007). Most of these deaths were caused by streptococcal toxic shock syndrome (STSS; Hu et al, 2000; Tang et al, 2006; Yu et al, 2006).
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