Candida albicans β-Glucan Exposure Is Controlled by the Fungal CEK1-Mediated Mitogen-Activated Protein Kinase Pathway That Modulates Immune Responses Triggered through Dectin-1
Candida albicans β-Glucan Exposure Is Controlled by the Fungal CEK1-Mediated Mitogen-Activated Protein Kinase Pathway That Modulates Immune Responses Triggered through Dectin-1
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DOI：
10.1128/iai.00989-09
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发表时间：
2010-04-01
影响因子：
3.1
通讯作者：
Fernandez-Ruiz, Elena
中科院分区：
文献类型：
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作者：
Galan-Diez, Marta;Arana, David M.;Fernandez-Ruiz, Elena
对白色念珠菌的先天免疫依赖于对真菌细胞壁上分子模式的识别。然而，掩盖主要成分，如β-葡聚糖似乎是真菌进化成通过Dectin-1受体来避免免疫细胞识别的机制。尽管白念珠菌丝裂原活化蛋白激酶(MAPK)通路作为毒力决定因素的作用已在动物模型中得到证实，但其作用机制仍不十分清楚。在这项研究中，我们证明了白念珠菌细胞外信号调节激酶(ERK)样蛋白1(CEK1)介导的MAPK通路的中断导致细胞壁β-葡聚糖暴露增加，通过Dectin-1介导的特异性结合以及人树突状细胞(HDC)和巨噬菌体介导的细胞内信号通路的吞噬、杀伤和激活来衡量，比野生型更有效地触发免疫反应。在分子水平上，CEK1的破坏导致脾酪氨酸激酶(Syk)、Raf-1和ERK1/2的激活改变，hDC上的I kappa B降解，并增加了转染细胞上Dectin-1依赖的激活蛋白1(AP-1)的激活。此外，伴随着这些途径的改变，我们检测到活性氧的产生和细胞因子的分泌增加。总之，CEK1介导的MAPK通路参与了真菌病原体对β-葡聚糖的暴露，从而影响依赖于Dectin-1的免疫细胞识别，从而建立了这一真菌细胞内信号通路作为一种有前景的新的治疗靶点。
Innate immunity to Candida albicans depends upon the recognition of molecular patterns on the fungal cell wall. However, the masking of major components such as beta-glucan seems to be a mechanism that fungi have evolved to avoid immune cell recognition through the dectin-1 receptor. Although the role of C. albicans mitogen-activated protein kinase (MAPK) pathways as virulence determinants has been established previously with animal models, the mechanism involved in this behavior is largely unknown. In this study we demonstrate that a disruption of the C. albicans extracellular signal-regulated kinase (ERK)-like 1 (CEK1)-mediated MAPK pathway causes enhanced cell wall beta-glucan exposure, triggering immune responses more efficiently than the wild type, as measured by dectin-1-mediated specific binding and human dendritic cell (hDC)- and macro-phage-mediated phagocytosis, killing, and activation of intracellular signaling pathways. At the molecular level, the disruption of CEK1 resulted in altered spleen tyrosine kinase (Syk), Raf-1, and ERK1/2 activations together with I kappa B degradation on hDCs and increased dectin-1-dependent activator protein 1 (AP-1) activation on transfected cells. In addition, concurring with these altered pathways, we detected increased reactive oxygen species production and cytokine secretion. In conclusion, the CEK1-mediated MAPK pathway is involved in beta-glucan exposure in a fungal pathogen, hence influencing dectin-1-dependent immune cell recognition, thus establishing this fungal intracellular signaling route as a promising novel therapeutic target.