Streptolysin O Promotes Group A Streptococcus Immune Evasion by Accelerated Macrophage Apoptosis
Streptolysin O Promotes Group A Streptococcus Immune Evasion by Accelerated Macrophage Apoptosis
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DOI：
10.1074/jbc.m804632200
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发表时间：
2009-01-09
影响因子：
4.8
通讯作者：
Nizet, Victor
中科院分区：
文献类型：
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作者：
Timmer, Anjuli M.;Timmer, John C.;Nizet, Victor
A群链球菌（GAS）是一种主要的人类细菌病原体，即使在以前健康的个体中也能产生侵袭性感染。巨噬细胞作为宿主先天防御的一线组分，在控制和清除GAS感染中起着关键作用。我们发现GAS诱导原代和培养的巨噬细胞和中性粒细胞快速、剂量依赖性的凋亡。细胞死亡途径涉及凋亡的caspase，部分依赖于caspase-1，并且需要吞噬细胞内化GAS。对GAS毒力因子突变体、异源表达和纯化毒素的分析表明，形成孔的细胞溶链霉素O （SLO）是诱导凋亡表型的必要和充分条件。在体外和体内，缺乏slow的GAS突变体诱导巨噬细胞凋亡较少，允许巨噬细胞细胞因子分泌，并且在小鼠全身感染模型中毒性较低。超微结构证据表明，线粒体膜重塑，再加上线粒体去极化和细胞色素c释放的丧失，表明毒素的直接攻击启动了内在的细胞凋亡途径。一种通用的caspase抑制剂阻断了slo诱导的凋亡，增强了巨噬细胞对GAS的杀伤。我们得出结论，由成孔细胞溶酶SLO诱导的加速的caspase依赖性巨噬细胞凋亡有助于GAS的免疫逃避和毒力。
Group A Streptococcus ( GAS) is a leading human bacterial pathogen capable of producing invasive infections even in previously healthy individuals. As frontline components of host innate defense, macrophages play a key role in control and clearance of GAS infections. We find GAS induces rapid, dose-dependent apoptosis of primary and cultured macrophages and neutrophils. The cell death pathway involves apoptotic caspases, is partly dependent on caspase-1, and requires GAS internalization by the phagocyte. Analysis of GAS virulence factor mutants, heterologous expression, and purified toxin studies identified the pore-forming cytolysin streptolysin O (SLO) as necessary and sufficient for the apoptosis-inducing phenotype. SLO-deficient GAS mutants induced less macrophage apoptosis in vitro and in vivo, allowed macrophage cytokine secretion, and were less virulent in a murine systemic infection model. Ultrastructural evidence of mitochondrial membrane remodeling, coupled with loss of mitochondrial depolarization and cytochrome c release, suggests a direct attack of the toxin initiates the intrinsic apoptosis pathway. A general caspase inhibitor blocked SLO-induced apoptosis and enhanced macrophage killing of GAS. We conclude that accelerated, caspase-dependent macrophage apoptosis induced by the pore-forming cytolysin SLO contributes to GAS immune evasion and virulence.