Uchiyama Satoshi, Döhrmann Simon, Timmer Anjuli M, Dixit Neha, Ghochani Mariam, Bhandari Tamara, Timmer John C, Sprague Kimberly, Bubeck-Wardenburg Juliane, Simon Scott I, Nizet Victor
Department of Pediatrics, University of California San Diego , La Jolla, CA , USA.
Department of Biomedical Engineering, University of California Davis , Davis, CA , USA.
Front Immunol. 2015 Nov 16;6:581. doi: 10.3389/fimmu.2015.00581. eCollection 2015.
Group A Streptococcus (GAS) causes a wide range of human infections, ranging from simple pharyngitis to life-threatening necrotizing fasciitis and toxic shock syndrome. A globally disseminated clone of M1T1 GAS has been associated with an increase in severe, invasive GAS infections in recent decades. The secreted GAS pore-forming toxin streptolysin O (SLO), which induces eukaryotic cell lysis in a cholesterol-dependent manner, is highly upregulated in the GAS M1T1 clone during bloodstream dissemination. SLO is known to promote GAS resistance to phagocytic clearance by neutrophils, a critical first element of host defense against invasive bacterial infection. Here, we examine the role of SLO in modulating specific neutrophil functions during their early interaction with GAS. We find that SLO at subcytotoxic concentrations and early time points is necessary and sufficient to suppress neutrophil oxidative burst, in a manner reversed by free cholesterol and anti-SLO blocking antibodies. In addition, SLO at subcytotoxic concentrations blocked neutrophil degranulation, interleukin-8 secretion and responsiveness, and elaboration of DNA-based neutrophil extracellular traps, cumulatively supporting a key role for SLO in GAS resistance to immediate neutrophil killing. A non-toxic SLO derivate elicits protective immunity against lethal GAS challenge in a murine infection model. We conclude that SLO exerts a novel cytotoxic-independent function at early stages of invasive infections (<30 min), contributing to GAS escape from neutrophil clearance.
A组链球菌（GAS）可引发多种人类感染，从简单的咽炎到危及生命的坏死性筋膜炎和中毒性休克综合征。近几十年来，一种在全球传播的M1T1 GAS克隆株与严重侵袭性GAS感染的增加有关。分泌型GAS成孔毒素链球菌溶血素O（SLO）以胆固醇依赖的方式诱导真核细胞裂解，在血流播散期间，GAS M1T1克隆株中其表达高度上调。已知SLO可促进GAS抵抗中性粒细胞的吞噬清除，这是宿主抵御侵袭性细菌感染的关键第一步。在此，我们研究了SLO在中性粒细胞与GAS早期相互作用过程中调节特定中性粒细胞功能的作用。我们发现，在亚细胞毒性浓度和早期时间点，SLO对于抑制中性粒细胞氧化爆发是必要且充分的，这种作用可被游离胆固醇和抗SLO阻断抗体逆转。此外，亚细胞毒性浓度的SLO可阻断中性粒细胞脱颗粒、白细胞介素-8分泌及反应性，以及基于DNA的中性粒细胞胞外陷阱的形成，这些结果共同支持SLO在GAS抵抗中性粒细胞即时杀伤中起关键作用。一种无毒的SLO衍生物在小鼠感染模型中可引发针对致死性GAS攻击的保护性免疫。我们得出结论，SLO在侵袭性感染的早期阶段（<30分钟）发挥一种新的非细胞毒性功能，有助于GAS逃避中性粒细胞的清除。
