Neutrophil Attack Triggers Extracellular Trap-Dependent Candida Cell Wall Remodeling and Altered Immune Recognition.
Neutrophil Attack Triggers Extracellular Trap-Dependent Candida Cell Wall Remodeling and Altered Immune Recognition.
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DOI：
10.1371/journal.ppat.1005644
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发表时间：
2016-05
期刊：
影响因子：
6.7
通讯作者：
Wheeler RT
中科院分区：
文献类型：
--
作者：
Hopke A;Nicke N;Hidu EE;Degani G;Popolo L;Wheeler RT
病原体隐藏免疫原性表位以逃避宿主免疫，持续存在并引起感染。机会性人类真菌病原体白色念珠菌（Candida albicans）可在免疫功能低下的患者群体中引起致命疾病，它提供了一个很好的例子，因为它掩盖了其细胞壁中的炎性表位β-葡聚糖，使其无法被宿主识别。先前已经证明，β-葡聚糖在体内感染期间暴露，但这种暴露背后的机制尚不清楚。在这里，我们发现这种暴露涉及中性粒细胞胞外陷阱（NET）介导的攻击，这引发了真菌细胞壁结构的变化，增强了Dectin-1 β-葡聚糖受体的体外免疫识别。此外，使用播散性念珠菌病的小鼠模型，我们证明了中性粒细胞在体内触发这些真菌细胞壁变化的要求。重要的是，我们发现，真菌表位解蔽需要一个积极的真菌反应，除了由中性粒细胞攻击提供的刺激。NET介导的损伤启动真菌MAP激酶驱动的反应，特别是通过Hog 1，动态重新定位细胞壁重塑机制，包括Chs 3，Phr 1和Sur 7。嗜中性粒细胞引发的细胞壁破坏增加了一些巨噬细胞对真菌攻击的细胞因子反应。这项工作提供了深入了解宿主-病原体相互作用在播散性念珠菌病，包括有价值的信息，如何C。白念珠菌细胞壁对免疫攻击的生物应激作出反应。我们的研究结果强调了重要的，但未得到充分重视的概念，感染过程中的模式识别是动态的，并依赖于宿主-病原体对话。机会性真菌感染，包括由C.白色念珠菌已经成为一个重要的全球健康负担，尽管有现代的抗真菌治疗，这些感染的传播形式仍然具有不可接受的高死亡率。真菌细胞壁控制其与宿主环境和免疫识别的相互作用，尽管对感染期间的细胞壁动力学知之甚少。C.白色念珠菌组织其细胞壁以掩盖炎性β-葡聚糖作为免疫逃避的一种形式，并且已知在感染期间该β-葡聚糖变得暴露。在这里，我们研究了β-葡聚糖是如何暴露的，并发现了一种动态的相互作用，其中宿主NET引发了活跃的真菌反应，破坏了细胞壁结构并暴露了β-葡聚糖。我们揭示了一个意想不到的水平的局部真菌细胞壁动态响应免疫介导的压力，这表明这可能代表了一个模型，可以利用来确定新的药物靶点。我们的研究结果突出了未充分研究的概念，即细胞壁是一个动态的景观感染过程中，可以受到主机。
Pathogens hide immunogenic epitopes from the host to evade immunity, persist and cause infection. The opportunistic human fungal pathogen Candida albicans, which can cause fatal disease in immunocompromised patient populations, offers a good example as it masks the inflammatory epitope β-glucan in its cell wall from host recognition. It has been demonstrated previously that β-glucan becomes exposed during infection in vivo but the mechanism behind this exposure was unknown. Here, we show that this unmasking involves neutrophil extracellular trap (NET) mediated attack, which triggers changes in fungal cell wall architecture that enhance immune recognition by the Dectin-1 β-glucan receptor in vitro. Furthermore, using a mouse model of disseminated candidiasis, we demonstrate the requirement for neutrophils in triggering these fungal cell wall changes in vivo. Importantly, we found that fungal epitope unmasking requires an active fungal response in addition to the stimulus provided by neutrophil attack. NET-mediated damage initiates fungal MAP kinase-driven responses, particularly by Hog1, that dynamically relocalize cell wall remodeling machinery including Chs3, Phr1 and Sur7. Neutrophil-initiated cell wall disruptions augment some macrophage cytokine responses to attacked fungi. This work provides insight into host-pathogen interactions during disseminated candidiasis, including valuable information about how the C. albicans cell wall responds to the biotic stress of immune attack. Our results highlight the important but underappreciated concept that pattern recognition during infection is dynamic and depends on the host-pathogen dialog. Opportunistic fungal infections, including those caused by C. albicans, have emerged as a significant global health burden and the disseminated form of these infections still have unacceptably high mortality rates despite modern antifungal treatments. The fungal cell wall controls its interaction with the host environment and immune recognition, although cell wall dynamics during infection are poorly understood. C. albicans organizes its cell wall to mask the inflammatory β-glucan as a form of immune evasion and it is known that during infection this β-glucan becomes exposed. Here, we investigated how β-glucan becomes exposed and discovered a dynamic interaction where host NETs provoke an active fungal response that disrupts cell wall architecture and unmasks β-glucan. We revealed an unexpected level of local fungal cell wall dynamics in response to immune mediated stress, suggesting this may represent a model that can be leveraged to identify novel drug targets. Our results highlight the understudied concept that the cell wall is a dynamic landscape during infection and can be influenced by the host.