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

我们的长期目标是了解宿主-病原体关系的分子基础，这种关系的特征是能够在宿主的良性定植中共生或增殖，导致包括假膜性和红斑性念珠菌病在内的一系列疾病表现。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在很大程度上是对宿主免疫受损的反应，这些受损是由于潜在的致衰性疾病(如艾滋病毒感染)或治疗干预(器官移植/化疗)造成的。此外，这种生长模式的转变是病原体的固有属性，它本身具有大量的毒力和致病特征(以及共生特征)，需要共生或增殖/侵袭生长。白念珠菌与其远缘非致病近缘酿酒酵母的基因组比较表明，白念珠菌含有200-235个呼吸代谢基因，这些基因在酿酒酵母中是没有的。其中很大一部分与脂肪酸和脂类的伯氧化有关。我们的假设是，这种氧化代谢的扩展遗传谱系反映了在体内定植和/或增殖过程中对这种类型过程的需求。此外，我们预计，如果在毒力生长中广泛使用氧化，则与实验室中通常使用的发酵代谢相比，一系列致病和毒力特征很可能在这些条件下表现出来。在我们的研究中，这种特征的候选者被确定为3-羟氧基脂(3-OH-oxlipins)，它是在多不饱和脂肪酸的氧化作用下合成的。我们的实验室已经证明，这类代谢物具有强大的生物活性，可以作为宿主免疫反应的脂类中介。因此，3-羟基氧基脂将确定它们在念珠菌细胞形态中的作用，并确定它们对细胞分化和其他功能的潜在影响，如交配。此外，本研究还将比较3-羟基氧基脂在调节与白念珠菌在宿主细胞中生存相关的信号通路中的具体作用。

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.