Pathogenicity factors of Malassezia furfur: genetic regulation of tryptophan-dependent secondary metabolites and their effect on immunocompetent and structural cells of human skin

以色氨酸为主要氮源时，马拉色菌能产生色素和荧光染料。这种新发现的代谢途径可能解释了一种常见的马拉色菌相关皮肤病--花斑癣（PV）的临床现象。迄今为止，已分离出18种化合物，其中14种在化学结构上是新的。它们具有有趣的药理学特性，例如紫外线防护（糠疹苷，糠疹内酯），刺激特异性抑制粒细胞的氧化爆发和树突状细胞的IL 12 p70释放（pityriarubins）、诱导人黑素细胞凋亡和激活芳烃受体以及诱导角质形成细胞中的细胞色素P450（马拉色菌素），与PV临床体征密切相关的性质。将通过生物测定进一步表征作用机制和作用特征。除了在黑色素瘤细胞中可能的凋亡诱导外，个体次级代谢产物对树突状细胞和单核细胞的影响以及刺激特异性爆发抑制的机制有待更详细地阐明。为了研究角质形成细胞、成纤维细胞和黑素细胞中的基因表达，将次级代谢产物用于皮肤特异性筛选cDNA微阵列。马拉色菌酵母中参与色素合成的基因将通过cDNA消减技术鉴定。通过证明花斑癣患者皮肤样本中相应的转录本，将研究所鉴定的基因在这种疾病中的相关性。

Malassezia yeasts can produce pigments and fluorochromes if tryptophan is offered as the main nitrogen source. This newly discovered metabolic pathway may explain clinical phenomena of pityriasis versicolor (PV), a common Malassezia-related skin disease. To date, 18 compounds have been isolated, of which 14 are new in terms of chemical structure. They have interesting pharmacological properties, such as UV protection (pityriacitrin, pityrialacton), stimulus-specific inhibition of the oxidative burst of granulocytes and IL12p70 release of dendritic cells (pityriarubins), induction of apoptosis in human melanocytes and activation of the arylhydrocarbon receptor as well as induction of cytochrome P450 in keratinocytes (malassezin), properties that are closely associated with clinical signs of PV. The mechanism and profile of action are to be further characterized by means of bioassays. Apart from a possible apoptosis induction in melanoma cells, the effect of individual secondary metabolites on dendritic and mononuclear cells and the mechanism of stimulus-specific burst inhibition are to be clarified in more detail. To investigate the gene expression in keratinocytes, fibroblasts and melanocytes, the secondary metabolites will be used in a skin-specific screening cDNA microarray. Genes of Malassezia yeasts that are involved in pigment synthesis will be identified by means of cDNA subtraction techniques. By demonstration of the corresponding transcripts in skin samples of patients with pityriasis versicolor the relevance of the identified genes in this disease is to be investigated.