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

如果提供色氨酸作为主要氮源，马拉色菌可以产生色素和荧光色素。这一新发现的代谢途径可能解释一种常见的马拉色菌相关皮肤病——花斑糠疹（PV）的临床现象。迄今为止，已分离出18种化合物，其中14种是化学结构上的新化合物。它们具有有趣的药理特性，如紫外线防护（pityriacitrin, pityrialacton），刺激特异性抑制粒细胞氧化爆发和树突状细胞IL12p70释放（pityriarubins），诱导人黑色素细胞凋亡，激活芳香烃受体以及诱导角质形成细胞细胞色素P450 (malassezin)，这些特性与PV的临床症状密切相关。其作用机制和作用谱将通过生物测定法进一步确定。除了可能诱导黑色素瘤细胞凋亡外，单个次级代谢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进一步阐明。为了研究基因在角质形成细胞、成纤维细胞和黑素细胞中的表达，将使用次级代谢物进行皮肤特异性筛选cDNA微阵列。利用cDNA减法技术对马拉色菌中参与色素合成的基因进行鉴定。通过在花斑糠疹患者的皮肤样本中显示相应的转录本，鉴定出的基因在这种疾病中的相关性将被调查。

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.