Neutrophil antimicrobial defense against Staphylococcus aureus is mediated by phagolysosomal but not extracellular trap-associated cathelicidin
Neutrophil antimicrobial defense against Staphylococcus aureus is mediated by phagolysosomal but not extracellular trap-associated cathelicidin
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DOI：
10.1189/jlb.0209053
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发表时间：
2009-11-01
影响因子：
5.5
通讯作者：
Landmann, Regine
中科院分区：
文献类型：
--
作者：
Jann, Naja J.;Schmaler, Mathias;Landmann, Regine
中性粒细胞通过AMP（包括cathelicidins、ROS和NET）杀死入侵的病原体。人类病原体金黄色葡萄球菌表现出对嗜中性粒细胞AMP（包括鼠凯萨林菌素CRAMP）的增强的抗性，部分是由于dlt操纵子对磷壁酸的丙氨酰化。本研究利用S.金黄色葡萄球菌Delta dltA对阳离子AMP的作用，以研究鼠凯萨林菌素CRAMP对葡萄球菌杀伤的影响，并鉴定其在鼠嗜中性粒细胞中的关键作用位点。我们证明，CRAMP保持在细胞内的PMN从血液中渗出，并分泌PMA刺激后。我们首次证明了CRAMP被募集到受感染的中性粒细胞的吞噬溶酶体中，并表现出细胞内抗链球菌的活性。金黄色。在感染后期，中性粒细胞产生NET，免疫荧光显示CRAMP与S。金黄色葡萄球菌在NET中，同样杀死了S.金黄色葡萄球菌wt和Δ dltA，表明当与NET相关时，CRAMP活性降低。事实上，DNA的存在降低了CRAMP的抗微生物活性，并降低了CRAMP对S.金黄色葡萄球菌是独立的NADPH氧化酶，而杀死是部分依赖于一个功能性的NADPH氧化酶。我们的研究表明，中性粒细胞在防御S。金黄色。J.利瓦克86：1159-1169; 2009.
Neutrophils kill invading pathogens by AMPs, including cathelicidins, ROS, and NETs. The human pathogen Staphylococcus aureus exhibits enhanced resistance to neutrophil AMPs, including the murine cathelicidin CRAMP, in part, as a result of alanylation of teichoic acids by the dlt operon. In this study, we took advantage of the hypersusceptible phenotype of S. aureus Delta dltA against cationic AMPs to study the impact of the murine cathelicidin CRAMP on staphylococcal killing and to identify its key site of action in murine neutrophils. We demonstrate that CRAMP remained intracellular during PMN exudation from blood and was secreted upon PMA stimulation. We show first evidence that CRAMP was recruited to phagolysosomes in infected neutrophils and exhibited intracellular activity against S. aureus. Later in infection, neutrophils produced NETs, and immunofluorescence revealed association of CRAMP with S. aureus in NETs, which similarly killed S. aureus wt and Delta dltA, indicating that CRAMP activity was reduced when associated with NETs. Indeed, the presence of DNA reduced the antimicrobial activity of CRAMP, and CRAMP localization in response to S. aureus was independent of the NADPH oxidase, whereas killing was partially dependent on a functional NADPH oxidase. Our study indicates that neutrophils use CRAMP in a timed and locally coordinated manner in defense against S. aureus. J. Leukoc. Biol. 86: 1159-1169; 2009.