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

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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.