Role of Proinflammatory Fungal Lipoids in Fungal Inflammation

多形核白细胞是宿主抵抗真菌感染的先天免疫防御的主要成分，提示真菌白细胞诱导剂和促炎细胞因子参与其中。我们在各种真菌中发现了不稳定的类脂类白细胞趋化剂，但在细菌或宿主细胞中没有发现。酵母的纯化、结构分析和化学合成表明，这些炎症介质是一个新的类脂家族的成员，它通过推测的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的脂类在真菌炎症中的作用，特别是在不同的病原真菌中通过质谱学鉴定这些类脂并调查其产生的条件。我们进一步观察到，酵母脂提取物可诱导角质形成细胞产生促炎细胞因子和趋化因子白介素8和RANTES。初步研究表明，这些类脂似乎至少在结构上与激活白细胞的类脂不同。因此，进一步的目的是阐明这些细胞因子诱导的真菌类脂的分子性质，并鉴定其可能的细胞受体。这些真菌特有的类脂，其宿主细胞受体，以及可能参与其生物合成的酶，可能是治疗真菌感染的新的抗炎治疗的靶点。

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.