A Second Stimulus Required for Enhanced Antifungal Activity of Human Neutrophils in Blood Is Provided by Anaphylatoxin C5a
A Second Stimulus Required for Enhanced Antifungal Activity of Human Neutrophils in Blood Is Provided by Anaphylatoxin C5a
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DOI：
10.4049/jimmunol.1401845
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发表时间：
2015-02-01
影响因子：
4.4
通讯作者：
Kurzai, Oliver
中科院分区：
文献类型：
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作者：
Huenniger, Kerstin;Bieber, Kristin;Kurzai, Oliver
中性粒细胞(PMN)作为天然免疫的细胞成分，在抵御系统性白念珠菌感染中起着至关重要的作用。为了在类似于活体的情况下分析白色念珠菌感染期间PMN活动所需的刺激，我们使用了人类全血感染模型。在该模型中，白念珠菌感染10min后PMN的激活在很大程度上依赖于过敏性毒素C5a。最重要的是，C5a使血液中的PMN克服了对白色念珠菌的细丝限制识别，并有效地从血液中消除了非丝状白色念珠菌cph1 Delta/efg1 Delta。主要的PMN效应机制，包括氧化爆发、次级颗粒内容物释放和初始真菌吞噬作用，可以通过阻断C5a受体信号来阻止。使用针对人C5a的人源化抗体也获得了相同的效果。白念珠菌感染后10min的吞噬作用是通过依赖C5a增强PMN表面CD11b的表达来实现的，从而确立了C5a-C5aR-CD11b轴是人类血液中早期抗白念珠菌免疫反应的主要调节器。相反，白念珠菌被PMN感染60min后的吞噬作用几乎独立于C5a而发生，并且主要是在以后的时间点激活吞噬活性的PMN。我们的结果表明，C5a是人类血液中白念珠菌感染过程中的关键介质。
Polymorphonuclear neutrophilic granulocytes (PMN) as cellular components of innate immunity play a crucial role in the defense against systemic Candida albicans infection. To analyze stimuli that are required for PMN activity during C. albicans infection in a situation similar to in vivo, we used a human whole-blood infection model. In this model, PMN activation 10 min after C. albicans infection was largely dependent on the anaphylatoxin C5a. Most importantly, C5a enabled blood PMN to overcome filament-restricted recognition of C. albicans and allowed efficient elimination of nonfilamentous C. albicans cph1 Delta/efg1 Delta from blood. Major PMN effector mechanisms, including oxidative burst, release of secondary granule contents and initial fungal phagocytosis could be prevented by blocking C5a receptor signaling. Identical effects were achieved using a humanized Ab specifically targeting human C5a. Phagocytosis of C. albicans 10 min postinfection was mediated by C5a-dependent enhancement of CD11b surface expression on PMN, thus establishing the C5a-C5aR-CD11b axis as a major modulator of early anti-Candida immune responses in human blood. In contrast, phagocytosis of C. albicans by PMN 60 min postinfection occurred almost independently of C5a and mainly contributed to activation of phagocytically active PMN at later time points. Our results show that C5a is a critical mediator in human blood during C. albicans infection.