Role of Proinflammatory Fungal Lipoids in Fungal Inflammation

多形核白细胞代表宿主先天免疫防御真菌感染的主要成分，表明真菌白细胞引诱剂和促炎细胞因子参与其中。我们在各种真菌中发现，但在细菌或宿主细胞中没有发现，不稳定的脂质样白细胞化学引诱剂。从酵母中纯化，结构分析和化学合成表明这些炎症介质是一类新的脂质家族的成员，它们通过假定的g蛋白偶联受体激活中性粒细胞。本项目的目的是研究这些不稳定脂质在真菌炎症中的作用，特别是通过质谱法在不同的致病真菌中鉴定这些脂质并研究其产生的条件。我们进一步观察到，酵母脂质提取物在角质形成细胞中诱导促炎细胞因子和趋化因子白介素-8和RANTES。初步研究表明，这些类脂至少在结构上与白细胞活化类脂部分不同。因此，进一步阐明这些诱导细胞因子的真菌类脂的分子性质并鉴定其可能的细胞受体是一个进一步的目标。这些真菌特异性脂质及其宿主细胞受体和可能参与其生物合成的酶可能是一种新的抗炎治疗真菌感染的靶点。

Polymorphonuclear leukocytes represent primary components of the host's innate immune defenses against fungal infection suggesting involvement of fungal leukocyte attractants and proinflammatory cytokines. We found in various fungi, but not in bacteria or host cells, unstable lipid-like leukocyte chemoattractants. Purification from yeast, structural analyses and chemical synthesis revealed these inflammatory mediators as members of a novel familiy of lipoids, which activate neutrophils via putative, G-protein-coupled receptors. It is the aim of this project to investigate the role of these unstable lipids in fungal inflammation, in particular to identify these lipoids by mass spectrometry in different pathogenic fungi and to investigate conditions of its production. We further observed, that yeast lipid extracts induced proinflammatory cytokines and the chemokines Interleukin-8 and RANTES in keratinocytes. Preliminary investigations showed, that these lipoids appear at least in part to be structurally different from leukocyte-activating lipoids. Therefore it is a further aim to elucidate the molecular nature of these cytokine-inducing fungal lipoids and to identify its putative cellular receptors. These fungus-specific lipoids, its host cell receptors and possibly the enzymes involved in its biosynthesis may be targets for a novel anti-inflammatory therapy in fungal infection.