Contribution of Nlrp3 Inflammasome Activation Mediated by Suilysin to Streptococcal Toxic Shock-like Syndrome.

Liqiong Song,Zhihong Ren,Yuanming Huang,Guangxun Meng,Yuchun Xiao,Yongqiang Jiang,Xianping Li

doi:10.3389/fmicb.2020.01788

Abstract

Objective: The aim of this study was to investigate the molecular mechanism of inflammasome activation in response to Streptococcus suis serotype 2 (SS2) infection and its contribution to the development of streptococcal toxic shock-like syndrome (STSS).Methods: To verify the role of suilysin (SLY) in STSS, we infected bone-marrow-derived macrophages (BMDMs) in vitro and C57BL/6J mice intraperitoneally (IP) with the SS2 wild-type (WT) strain or isogenic sly mutant (∆SLY) to measure the interleukin (IL)-1β release and survival rate. To determine the role of inflammasome activation and pyroptosis in STSS, we infected BMDMs from WT and various deficient mice, including Nlrp3-deficient (Nlrp3−/−), Nlrc4-deficient (Nlrc4−/−), Asc-deficient (Asc−/−), Aim2-deficient (Aim2−/−), Caspase-1/11-deficient (Caspase-1/11−/−), and Gsdmd-deficient (Gsdmd−/−) ex vivo, and IP injected WT, Nlrp3−/−, Caspase-1/11−/−, and Gsdmd−/− mice with SS2, to compare the IL-1β releases and survival rate in vivo.Results: The SS2-induced IL-1β production in mouse macrophages is mediated by SLY ex vivo. The survival rate of WT mice infected with SS2 was significantly lower than that of mice infected with the ∆SLY strain in vivo. Furthermore, SS2-triggered IL-1β releases, and the cytotoxicity in the BMDMs required the activation of the NOD-Like Receptors Family Pyrin Domain Containing 3 (Nlrp3), Caspase-1/11, and gasdermin D (Gsdmd) inflammasomes, but not the Nlrc4 and Aim2 inflammasomes ex vivo. The IL-1β production and survival rate of WT mice infected with SS2 were significantly lower than those of the Nlrp3−/−, Caspase-1/11−/−, and Gsdmd−/− mice in vivo. Finally, the inhibitor of the Nlrp3 inflammasome could reduce the IL-1β release and cytotoxicity of SS2-infected macrophages ex vivo and protect SS2-infected mice from death in vivo.Conclusion: Nlrp3 inflammasome activation triggered by SLY in macrophages played an important role in the pathogenesis of STSS.

Highlights

Streptococcus suis is a common swine pathogen, which results in a great loss to swine industry every year and causes meningitis and streptococcal toxic shock-like syndrome (STSS) in humans (Ye et al, 2006; Yu et al, 2006; Gottschalk et al, 2007; Huong et al, 2014)
suis serotype 2 (SS2)-triggered Interlukin 1β (IL-1β) releases, and the cytotoxicity in the bone-marrow-derived macrophages (BMDMs) required the activation of the NOD-Like Receptors Family Pyrin Domain Containing 3 (Nlrp3), Caspase-1/11, and gasdermin D (Gsdmd) inflammasomes, but not the Nlrc4 and Aim2 inflammasomes ex vivo
The IL-1β production and survival rate of WT mice infected with SS2 were significantly lower than those of the Nlrp3−/−, Caspase-1/11−/−, and Gsdmd−/− mice in vivo

Summary

Introduction

Streptococcus suis is a common swine pathogen, which results in a great loss to swine industry every year and causes meningitis and streptococcal toxic shock-like syndrome (STSS) in humans (Ye et al, 2006; Yu et al, 2006; Gottschalk et al, 2007; Huong et al, 2014). ST7 is thought to have been responsible for two large outbreaks of human SS2 infections in China in 1998 and 2005 (Hu et al, 2000; Ye et al, 2006; Yu et al, 2006). The serum proinflammatory cytokines in STSS patients, especially interleukin 6 (IL-6), IL-1β, and tumor necrosis factor (TNF), gamma interferon (IFN-ɣ), IL-12, and monocyte chemoattractant protein 1 (MCP-1), are significantly higher than those in meningitis patients (Ye et al, 2009). How the overproduction of proinflammatory cytokines occurs in STSS is not fully understood

Methods

Results

Conclusion