NOD2 contributes to cutaneous defense against Staphylococcus aureus through α-toxin-dependent innate immune activation
NOD2 contributes to cutaneous defense against Staphylococcus aureus through α-toxin-dependent innate immune activation
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DOI：
10.1073/pnas.0904958106
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发表时间：
2009-08-04
影响因子：
11.1
通讯作者：
Eckmann, Lars
中科院分区：
文献类型：
--
作者：
Hruz, Petr;Zinkernagel, Annelies S.;Eckmann, Lars
金黄色葡萄球菌是社区获得性和医院感染的主要原因，包括危及生命的心内膜炎、坏死性肺炎、坏死性筋膜炎和败血症。toll样受体(TLR)-2是一种膜结合的微生物传感器，可检测葡萄球菌成分，但缺乏TLR2或TLR2和TLR4的巨噬细胞仍对金黄色葡萄球菌有反应，这表明可能涉及另一种微生物识别受体。胞质传感器核苷酸结合寡聚化结构域（NOD） 2/caspase募集结构域（CARD） 15)在体外检测细菌肽聚糖中的muramyl二肽并介导对金黄色葡萄球菌的细胞因子反应，但这些观察结果的生理意义尚不明确。本研究表明，在金黄色葡萄球菌感染后，nod2缺陷小鼠表现出延迟但最终加重的溃疡反应和细菌清除受损。金黄色葡萄球菌和muramyl二肽的nod2依赖性识别是由α -毒素（α溶血素）促进的，α -毒素是病原体的一种成孔毒素和毒力因子。NOD2的作用依赖于IL-1 β扩增的IL-6的产生，IL-6促进中性粒细胞快速杀死细菌。这些结果显著拓宽了NOD2在先天免疫中的生理重要性，从识别主要进入细胞质的细菌到检测通常存在于细胞外的细菌，并证明这种微生物传感器有助于区分共生细菌和细菌病原体。
Staphylococcus aureus is a major cause of community-acquired and nosocomial infections including the life-threatening conditions endocarditis, necrotizing pneumonia, necrotizing fasciitis, and septicemia. Toll-like receptor (TLR)-2, a membrane-bound microbial sensor, detects staphylococcal components, but macrophages lacking TLR2 or both TLR2 and TLR4 remain S. aureus responsive, suggesting that an alternative microbial recognition receptor might be involved. The cytoplasmic sensor nucleotide-binding oligomerization domain containing (NOD) 2/caspase recruitment domain (CARD) 15 detects muramyl dipeptide from bacterial peptidoglycans and mediates cytokine responses to S. aureus in vitro, but the physiological significance of these observations is not well defined. Here we show that NOD2-deficient mice exhibit a delayed but ultimately exacerbated ulcerative response and impaired bacterial clearance after s.c. infection with S. aureus. NOD2-dependent recognition of S. aureus and muramyl dipeptide is facilitated by alpha-toxin (alpha-hemolysin), a pore-forming toxin and virulence factor of the pathogen. The action of NOD2 is dependent on IL-1 beta-amplified production of IL-6, which promotes rapid bacterial killing by neutrophils. These results significantly broaden the physiological importance of NOD2 in innate immunity from the recognition of bacteria that primarily enter the cytoplasm to the detection of bacteria that typically reside extracellularly and demonstrate that this microbial sensor contributes to the discrimination between commensal bacteria and bacterial pathogens that elaborate poreforming toxins.