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首页> 外文学位 >B. anthracis peptidoglycan activates human innate immune cells and platelets through Fcgamma receptors and complement proteins.
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B. anthracis peptidoglycan activates human innate immune cells and platelets through Fcgamma receptors and complement proteins.

机译：炭疽芽孢杆菌肽聚糖通过Fcγ受体和补体蛋白激活人类先天免疫细胞和血小板。

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摘要

Gram-positive bacteria are an important public health problem, but it is unclear how they cause systemic inflammation. Our previous work showed that peptidoglycan (PGN) derived from the Gram-positive pathogen, Bacillus anthracis, induced proinflammatory cytokines in human cells by binding an unknown extracellular receptor followed by phagocytosis and stimulation of cytoplasmic NOD receptors. We used flow cytometry to identify host factors that supported PGN binding to immune cells. PGN binding required plasma and plasma from all tested healthy donors contained IgG recognizing PGN. Plasma depleted of IgG or of anti-PGN did not support PGN binding or PGN-triggered cytokine production. Adding back intact but not F(ab')2 IgG restored binding and cytokine production. Transfection of HEK293 cells with FcgammaRIIA enabled PGN binding and phagocytosis.;Platelet activation frequently accompanies sepsis and contributes to the sepsis-associated vascular leakage and coagulation dysfunction. We used flow cytometry and fluorescent microscopy to define the effects of peptidoglycan (PGN) on the activation of human platelets. We found that PGN induced platelet aggregation, expression of the activated form of integrin alphaIIbbeta3, and exposure of phosphatidylserine (PS). These changes were dependent on IgG and were attenuated by the FcgammaRIIa-blocking antibody IV.3, suggesting they are mediated by PGN-anti-PGN immune complexes signaling through FcgammaRIIa. PS exposure was not blocked by IV.3 but was sensitive to inhibitors of complement activation. PGN was a potent activator of the classical complement cascade in human plasma and caused deposition of C5b-9 on the platelet surface. Platelets with exposed PS had greatly accelerated prothrombinase activity.;Our results establish a key role for anti-PGN IgG and FcgammaRs in supporting inflammation to gram-positive PGN and suggest anti-PGN IgG contributes to human pathology in Gram-positive sepsis. We also find that peptidoglycan derived from Gram-positive bacteria is a potent platelet agonist and could contribute to the coagulation dysfunction accompanying Gram-positive infections.
机译：革兰氏阳性细菌是重要的公共卫生问题，但目前尚不清楚它们如何引起全身性炎症。我们以前的工作表明，源自革兰氏阳性病原体炭疽杆菌的肽聚糖（PGN）通过结合未知的细胞外受体，然后吞噬和刺激细胞质NOD受体，在人细胞中诱导促炎性细胞因子。我们使用流式细胞仪来鉴定支持PGN与免疫细胞结合的宿主因子。 PGN结合需要血浆，并且所有测试的健康供体的血浆均含有识别PGN的IgG。血浆中的IgG或抗PGN耗尽，不支持PGN结合或PGN触发的细胞因子产生。加入完整但不是F（ab'）2 IgG可以恢复结合和细胞因子的产生。用FcgRIRIIA转染HEK293细胞可实现PGN结合和吞噬作用。脓毒症常伴有血小板活化，并引起脓毒症相关的血管渗漏和凝血功能障碍。我们使用流式细胞仪和荧光显微镜来定义肽聚糖（PGN）对人类血小板活化的影响。我们发现PGN诱导血小板聚集，整联蛋白alphaIIbbeta3活化形式的表达以及磷脂酰丝氨酸（PS）的暴露。这些变化取决于IgG，并被FcgammaRIIa阻断抗体IV.3减弱，表明它们是通过FcgammaRIIa的PGN-抗-PGN免疫复合物介导的。 PS暴露不受IV.3阻断，但对补体激活抑制剂敏感。 PGN是人血浆中经典补体级联的有效活化剂，并导致C5b-9沉积在血小板表面。暴露于PS的血小板极大地促进了凝血酶原酶的活性。;我们的结果确立了抗PGN IgG和FcgammaR在支持革兰氏阳性PGN炎症中的关键作用，并表明抗PGN IgG有助于革兰氏阳性脓毒症的人类病理。我们还发现，源自革兰氏阳性细菌的肽聚糖是一种有效的血小板激动剂，可能会导致伴随革兰氏阳性感染的凝血功能障碍。

著录项

  • 作者

    Sun, Dawei.;

  • 作者单位

    The University of Oklahoma Health Sciences Center.;

  • 授予单位 The University of Oklahoma Health Sciences Center.;
  • 学科 Immunology.;Cellular biology.;Microbiology.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 177 p.
  • 总页数 177
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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