Role of phospholipomannan in Candida albicans escape from macrophages and induction of cell apoptosis through regulation of bad phosphorylation
Role of phospholipomannan in Candida albicans escape from macrophages and induction of cell apoptosis through regulation of bad phosphorylation
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DOI：
10.1196/annals.1299.107
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发表时间：
2003-01-01
期刊：
影响因子：
--
通讯作者：
Jouault, T
中科院分区：
文献类型：
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作者：
Ibata-Ombetta, S;Idziorek, T;Jouault, T
白色念珠菌是人类最常见的机会性真菌病原体，是正常微生物菌群的一部分。为了研究与这种酵母菌的共生-病原体转换相关的宿主-寄生虫相互作用，我们比较了巨噬细胞对白色念珠菌和非致病性酿酒酵母的反应。与酿酒酵母相反，白色念珠菌在巨噬细胞内存活。巨噬细胞的这种逃逸与吞噬过程中MEK、ERK1/2和p90RSK顺序磷酸化的定性差异有关。在白色念珠菌中观察到该途径的激活降低，并与MEK磷酸酶MKP-1的物种特异性过表达有关。白色念珠菌对ERK1/2/p90RSK信号转导通路的失调与Bad磷酸化的降低（特别是Ser-112）和游离Bcl-2的消失有关。通过巨噬细胞外膜暴露的磷脂酰丝氨酸染色显示，摄取白色念珠菌的细胞凋亡结束。磷脂甘露聚糖（PLM）是一种系统发育上独特的糖脂，具有白色念珠菌表面和脱落的植物神经酰胺片段，研究了它的作用。将PLM添加到巨噬细胞中导致与活的白色念珠菌相似的失调，并促进细胞内敏感的酿酒葡萄球菌的存活。在巨噬细胞与PLM孵育后，膜磷脂酰丝氨酸外化、线粒体完整性丧失和DNA断裂的证据表明，该分子支持在白色念珠菌酵母细胞中观察到的活性。
Candida albicans, the most common opportunistic fungal pathogen of humans is a part of the normal microbial flora. To investigate host-parasite interaction related to the commensal-pathogen switch of this yeast we compared the response of macrophages to C. albicans and to the non-pathogenic yeast Saccharomyces cerevisiae. In contrast to S. cerevisiae, C. albicans survived within macrophages. This escape from macrophages was associated with qualitative differences in the sequential phosphorylation of MEK, ERK1/2, and p90RSK during phagocytosis. Decreased activation of this pathway was observed with C. albicans and was associated with a species-specific overexpression of the MEK phosphatase, MKP-1. Dysregulation of the ERK1/2/p90RSK signal transduction pathway by C. albicans was associated downstream with reduction in Bad phosphorylation, specifically at Ser-112, and disappearance of free Bcl-2. This ended at apoptosis of cells that have ingested C. albicans, as revealed by staining of phosphatidylserine exposure in the macrophage outer membrane. The role of phospholipomannan (PLM), a phylogenetically unique glycolipid with a phytoceramide moiety expressed at the surface of and shed by C albicans, was examined. Addition of PLM to macrophages led to dysregulation similar to that observed with live C albicans and promoted the survival of the sensitive S. cerevisiae within the cells. Evidence of externalization of membranous phosphatidylserine, loss of mitochondrial integrity, and DNA fragmentation after incubation of macrophages with PLM suggest that this molecule supported the activities observed with C albicans yeast cells.