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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >NOD2 contributes to cutaneous defense against Staphylococcus aureus through α-toxin-dependent innate immune activation
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NOD2 contributes to cutaneous defense against Staphylococcus aureus through α-toxin-dependent innate immune activation

机译:NOD2通过依赖于α毒素的先天免疫激活来促进针对金黄色葡萄球菌的皮肤防御

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摘要

Staphylococcus aureus is a major cause of community-acquired and nosocomial infections including the life-threatening conditions endocarditis, necrotizing pneumonia, necrotizing fasciitis, and sep-ticemia. Toll-like receptor (TLR)-2, a membrane-bound microbial sensor, detects staphylococcal components, but macrophages lacking TLR2 or both TLR2 and TLR4 remain 5. 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 pep-tidoglycans 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 α-toxin (α-hemolysin), a pore-forming toxin and virulence factor of the pathogen. The action of NOD2 is dependent on IL-1β-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 pore-forming toxins.
机译:金黄色葡萄球菌是社区获得性和医院感染的主要原因,包括危及生命的疾病,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是一种与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敏感,这表明可能与另一种微生物识别受体有关。包含(NOD)2 /半胱天冬酶募集结构域(CARD)15的胞质传感器核苷酸结合寡聚结构域可检测细菌pep-tidoglycans中的嘧啶二肽并介导细胞因子对金黄色葡萄球菌的体外反应,但这些观察结果的生理意义并不理想定义。在这里,我们显示NOD2缺陷型小鼠在s.c.后表现出延迟但最终加剧的溃疡反应和受损的细菌清除。金黄色葡萄球菌感染。 α-毒素(α-溶血素)促进了NOD2的金黄色葡萄球菌和嘧啶二肽的识别,α-毒素是病原体的致孔毒素和致病因子。 NOD2的作用取决于IL-1β扩增的IL-6产生,该产生促进嗜中性粒细胞迅速杀死细菌。这些结果极大地拓宽了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,证明了这种微生物传感器有助于区分共生细菌和细化孔的细菌病原体形成毒素。

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  • 作者单位

    Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093;

    Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093;

    Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093;

    Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093;

    Institut National de la Sante et de la Recherche Medicale, U843, Universite Paris 7, Hopital Robert Debre, 75019 Paris, France;

    Laboratory of Gene Expression and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093;

    Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093;

    Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    innate immunity; interleukin-1; interleukin-6; microbial pathogenesis;

    机译:先天免疫;白介素1;白介素6;微生物发病机理;

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