Role of 3-hydroxyoxylipins, novel fungal metabolites of arachidonic acid, in Candida infection: potent effectors of fungal growth, virulence, and host cell survival

3-羟基氧基脂质（花生四烯酸的新型真菌代谢物）在念珠菌感染中的作用：真菌生长、毒力和宿主细胞存活的有效效应器

• 批准号: 5426978
• 负责人: Dr. Santosh Nigam (†)
• 金额: --
• 依托单位: Klinik für Gynäkologie (CBF)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2004
• 资助国家: 德国
• 起止时间: 2003-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5426978?language=en
• 关键词: Role; hydroxyoxylipins; novel; fungal; metabolites

Our long term objective is to understand the molecular basis of the host-pathogen relationship, which has as its hallmarks, the ability to exist commensally in a benign colonization of its host or to grow proliferatively, causing a spectrum of disease manifestations including pseudomembranous and erythematous candidiasis. These forms of candidiasis have primarily been studied in oral and vaginal mucosal infections. The transition from benign to pathogenic is largely in response to impaired host immunity brought about either as a result of underlying debilitating disease (e.g. HIV infection) or therapeutic intervention (organ transplantation/chemotherapy). Furthermore, this transition in growth pattern is an innate property of the pathogen which itself has an arsenal of virulence and pathogenesis traits (as well as commensal traits) which it calls upon for either commensal or proliferative/invasive growth. Genomic comparisons between C. albicans and its distant nonpathogenic relative, S. cerevisiae reveal that C. albicans contains an expanded repertoire of 200-235 genes in respiratory metabolism, which are not found in S. cerevisiae. A large fraction of these are related to the ß-oxidation of fatty acids and lipids. It is our hypothesis that this expanded genetic repertoire for oxidative metabolism reflects a need for this type of process in vivo during colonization and/or proliferation. Furthermore, we expect that if ß-oxidation is widely used in virulent growth, a range of pathogenesis and virulence traits are likely to be expressed in these conditions, as compared with those of fermentative metabolism which are generally used in laboratory settings. Candidates for such a trait were identified in our studies as 3-hydroxyoxylipins (3-OH-oxylipins), which are synthesized as function of the ß-oxidation of polyunsaturated fatty acids. Our laboratory has shown that metabolites of this class are known to have potent biological activity as lipid-derived mediators of the host immune response. Thus, 3-OH-oxylipins will define their role in cell morphology of Candida and identify their potential effects on cell differentiation and other functions, such as mating. In addition, the present study will compare the specific contribution of 3-OH-oxylipins to the modulation of signaling pathways linked to the survival of C. albicans in the host cell.

我们的长期目标是了解宿主-病原体关系的分子基础，其特征是能够在宿主的良性定殖中寄生存在或增殖生长，引起一系列疾病表现，包括假膜性和寄生性念珠菌病。这些形式的念珠菌病主要在口腔和阴道粘膜感染中进行研究。从良性到致病性的转变主要是由于潜在的衰弱性疾病（如HIV感染）或治疗干预（器官移植/化疗）导致的宿主免疫力受损。此外，这种生长模式的转变是病原体的固有特性，病原体本身具有毒力和致病性状（以及寄生性状），它需要这些毒力和致病性状用于寄生或增殖/侵入生长。C. albicans及其非致病性远亲S. cerevisiae表明C.白念珠菌在呼吸代谢中包含200-235个基因，这在S.啤酒。其中很大一部分与脂肪酸和脂质的反式氧化有关。这是我们的假设，这种扩大的基因库氧化代谢反映了需要这种类型的过程中，在体内定植和/或增殖。此外，我们预计，如果β-氧化被广泛用于毒性生长，一系列的发病机制和毒力性状可能会在这些条件下表达，与那些通常用于实验室环境中的发酵代谢。在我们的研究中，这种性状的候选者被鉴定为3-羟基氧脂（3-OH-氧脂），其是作为多不饱和脂肪酸的α-氧化的功能合成的。我们的实验室已经表明，这类代谢物已知具有有效的生物活性，作为宿主免疫反应的脂质衍生介质。因此，3-OH-氧脂将定义其在念珠菌细胞形态中的作用，并确定其对细胞分化和其他功能（如交配）的潜在影响。此外，本研究将比较3-OH-氧化脂质对与C.白色念珠菌在宿主细胞中。