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Pathogenic Yeasts Cryptococcus neoformans and Candida albicans Produce Immunomodulatory Prostaglandins

机译:病原酵母新隐球菌和白色念珠菌可产生免疫调节性前列腺素。

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摘要

Enhanced prostaglandin production during fungal infection could be an important factor in promoting fungal colonization and chronic infection. Host cells are one source of prostaglandins; however, another potential source of prostaglandins is the fungal pathogen itself. Our objective was to determine if the pathogenic yeasts Cryptococcus neoformans and Candida albicans produce prostaglandins and, if so, to begin to define the role of these bioactive lipids in yeast biology and disease pathogenesis. C. neoformans and C. albicans both secreted prostaglandins de novo or via conversion of exogenous arachidonic acid. Treatment with cyclooxygenase inhibitors dramatically reduced the viability of the yeast and the production of prostaglandins, suggesting that an essential cyclooxygenase like enzyme may be responsible for fungal prostaglandin production. A PGE series lipid was purified from both C. albicans and C. neoformans and was biologically active on both fungal and mammalian cells. Fungal PGEx and synthetic PGE2 enhanced the yeast-to-hypha transition in C. albicans. Furthermore, in mammalian cells, fungal PGEx down-modulated chemokine production, tumor necrosis factor alpha production, and splenocyte proliferation while up-regulating interleukin 10 production. These are all activities previously documented for mammalian PGE2. Thus, eicosanoids are produced by pathogenic fungi, are critical for growth of the fungi, and can modulate host immune functions. The discovery that pathogenic fungi produce and respond to immunomodulatory eicosanoids reveals a virulence mechanism that has potentially great implications for understanding the mechanisms of chronic fungal infection, immune deviation, and fungi as disease cofactors.
机译:真菌感染过程中前列腺素产生的增加可能是促进真菌定植和慢性感染的重要因素。宿主细胞是前列腺素的一种来源。然而,前列腺素的另一个潜在来源是真菌病原体本身。我们的目标是确定致病性酵母新隐球菌和白色念珠菌是否产生前列腺素,如果是,则开始确定这些生物活性脂质在酵母生物学和疾病发病机理中的作用。 C. neoformans和C. albicans都从头分泌前列腺素或通过外源花生四烯酸的转化而分泌。用环氧合酶抑制剂处理会大大降低酵母的活力和前列腺素的产生,这表明一种必需的环氧合酶类酶可能是导致真菌前列腺素产生的原因。 PGE系列脂质从白色念珠菌和新孢梭菌中纯化,对真菌和哺乳动物细胞均具有生物活性。真菌PGEx和合成的PGE2增强了白色念珠菌中酵母菌到菌丝的转化。此外,在哺乳动物细胞中,真菌PGEx下调趋化因子的产生,肿瘤坏死因子α的产生和脾细胞增殖,同时上调白介素10的产生。这些都是先前针对哺乳动物PGE2记录的活动。因此,类花生酸是由致病性真菌产生的,对真菌的生长至关重要,并且可以调节宿主的免疫功能。病原性真菌产生并响应免疫调节类花生酸的发现揭示了一种毒力机制,该机制对于理解慢性真菌感染,免疫偏离和真菌作为疾病辅助因子的机制具有潜在的重大意义。

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