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

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

JOURNAL=Frontiers in Microbiology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2020.01788

DOI=10.3389/fmicb.2020.01788

ISSN=1664-302X

ABSTRACT=<p><bold>Objective</bold>: The aim of this study was to investigate the molecular mechanism of inflammasome activation in response to <italic>Streptococcus suis</italic> serotype 2 (SS2) infection and its contribution to the development of streptococcal toxic shock-like syndrome (STSS).</p><p><bold>Methods</bold>: To verify the role of suilysin (SLY) in STSS, we infected bone-marrow-derived macrophages (BMDMs) <italic>in vitro</italic> and C57BL/6J mice intraperitoneally (IP) with the SS2 wild-type (WT) strain or isogenic <italic>sly</italic> 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 <italic>Nlrp3</italic>-deficient (Nlrp3<sup>−/−</sup>), <italic>Nlrc4</italic>-deficient (Nlrc4<sup>−/−</sup>), <italic>Asc</italic>-deficient (Asc<sup>−/−</sup>), <italic>Aim2</italic>-deficient (Aim2<sup>−/−</sup>), <italic>Caspase</italic>-1/11-deficient (Caspase-1/11<sup>−/−</sup>), and <italic>Gsdmd</italic>-deficient (Gsdmd<sup>−/−</sup>) <italic>ex vivo</italic>, and IP injected WT, Nlrp3<sup>−/−</sup>, Caspase-1/11<sup>−/−</sup>, and Gsdmd<sup>−/−</sup> mice with SS2, to compare the IL-1β releases and survival rate <italic>in vivo</italic>.</p><p><bold>Results</bold>: The SS2-induced IL-1β production in mouse macrophages is mediated by SLY <italic>ex vivo</italic>. The survival rate of WT mice infected with SS2 was significantly lower than that of mice infected with the ∆SLY strain <italic>in vivo</italic>. 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 <italic>ex vivo</italic>. The IL-1β production and survival rate of WT mice infected with SS2 were significantly lower than those of the Nlrp3<sup>−/−</sup>, Caspase-1/11<sup>−/−</sup>, and Gsdmd<sup>−/−</sup> mice <italic>in vivo</italic>. Finally, the inhibitor of the Nlrp3 inflammasome could reduce the IL-1β release and cytotoxicity of SS2-infected macrophages <italic>ex vivo</italic> and protect SS2-infected mice from death <italic>in vivo</italic>.</p><p><bold>Conclusion</bold>: Nlrp3 inflammasome activation triggered by SLY in macrophages played an important role in the pathogenesis of STSS.</p>