Toll-like receptor 4 confers inflammatory response to Suilysin.

Lili Bi,Yaya Pian,Qingyu Lv,Peng Liu,Yuling Zheng,Yuan Yuan,Shengwei Zhang,Shaolong Chen,Huaijie Hao,Yongqiang Jiang,Zhiqiang Ren

doi:10.3389/fmicb.2015.00644

Abstract

Streptococcus suis serotype 2 (SS2) is an emerging human pathogen worldwide. A large outbreak occurred in the summer of 2005 in China. Serum samples from this outbreak revealed that levels of the main proinflammatory cytokines were significantly higher in patients with streptococcal toxic-shock-like syndrome (STSLS) than in patients with meningitis only. However, the mechanism underlying the cytokine storm in STSLS caused by SS2 remained unclear. In this study, we found that suilysin (SLY) is the main protein inflammatory stimulus of SS2 and that native SLY (nSLY) stimulated cytokines independently of its haemolytic ability. Interestingly, a small amount of SLY (Å Mol/L) induced strong, long-term TNF-α release from human PBMCs. We also found that nSLY stimulated TNF-α in wild-type macrophages but not in macrophages from mice that carried a spontaneous mutation in TLR4 (P712H). We demonstrated for the first time that SLY stimulates immune cells through TLR4. In addition, the Myd88 adaptor-p38-MAPK pathway was involved in this process. The present study suggested that the TLR4-dependent inflammatory responses induced by SLY in host might contribute to the STSLS caused by SS2 and that p38-MAPK could be used as a target to control the release of excess TNF-α induced by SS2.

Highlights

The Gram-positive bacterium Strptococcus suis serotype 2 (SS2) can cause a systemic infection in humans; sepsis and meningitis are the most common clinical manifestations (Tang et al, 2006; Wangkaew et al, 2006; Huong et al, 2014)
SLY is the Main S. suis Protein That Stimulates Inflammation To identify the inflammatory stimulus of S. suis, several genes encoding potential virulence factors, including SLY (12), MRP
The streptococcal toxic shock like syndrome (STSLS) in the large S. suis outbreak in 2005 in China caused a high incidence of morbidity and mortality despite antibiotic therapy (Sriskandan and Slater, 2006)

Summary

Introduction

The Gram-positive bacterium Strptococcus suis serotype 2 (SS2) can cause a systemic infection in humans; sepsis and meningitis are the most common clinical manifestations (Tang et al, 2006; Wangkaew et al, 2006; Huong et al, 2014). In 2005, China reported more than 200 human cases with an unusual clinical presentation of STSLS and a mortality rate of up to 20% (Sriskandan and Slater, 2006). Serum samples revealed that TNF-α, IL-6,IL-1β, IL-8, IL-12p70 and IFN-γ were significantly higher in patients with STSLS than in those with meningitis (Ye et al, 2009). It was reported that cell walls and SLY can activate endothelial cells to release cytokines (Vadeboncoeur et al, 2003). SLY is a 497 amino-acid protein belonging to the cholesterol-dependent cytolysin (CDC) family, which has more than 20 members, including

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