Hünniger Kerstin, Bieber Kristin, Martin Ronny, Lehnert Teresa, Figge Marc Thilo, Löffler Jürgen, Guo Ren-Feng, Riedemann Niels C, Kurzai Oliver
Septomics Research Center, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, 07745 Jena, Germany;
Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, 07745 Jena, Germany; Friedrich Schiller University Jena, 07743 Jena, Germany;
J Immunol. 2015 Feb 1;194(3):1199-210. doi: 10.4049/jimmunol.1401845. Epub 2014 Dec 24.
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 cph1Δ/efg1Δ 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.
多形核嗜中性粒细胞（PMN）作为固有免疫的细胞成分，在抵御系统性白色念珠菌感染中发挥着关键作用。为了在类似于体内的情况下分析白色念珠菌感染期间PMN活性所需的刺激因素，我们使用了人全血感染模型。在该模型中，白色念珠菌感染10分钟后PMN的激活很大程度上依赖于过敏毒素C5a。最重要的是，C5a使血液中的PMN能够克服对白色念珠菌菌丝受限的识别，并允许从血液中有效清除非丝状的白色念珠菌cph1Δ/efg1Δ。通过阻断C5a受体信号传导，可以阻止包括氧化爆发、次级颗粒内容物释放和初始真菌吞噬作用在内的主要PMN效应机制。使用特异性靶向人C5a的人源化抗体也能达到相同的效果。感染后10分钟白色念珠菌的吞噬作用是由C5a依赖性增强PMN上CD11b表面表达介导的，从而确立了C5a - C5aR - CD11b轴作为人血中早期抗念珠菌免疫反应的主要调节因子。相比之下，感染后60分钟PMN对白色念珠菌的吞噬作用几乎独立于C5a，并且主要在后期促进吞噬活性PMN的激活。我们的结果表明，C5a是白色念珠菌感染期间人血中的关键介质。
