Pathogenic yeasts Cryptococcus neoformans and Candida albicans produce immunomodulatory prostaglandins

Enhanced prostoglandin production during fungal infection could be an impor tant factor in promoting fungal colonization and chronic infection. Host ce lls are one source of prostaglandins; however, another potential source of prostaglandins is the fungal pathogen itself. Our objective was to determin e if the pathogenic yeasts Cryptococcus neoformans and Candida albicans pro duce prostaglandins and, if so, to begin to define the role of these bioact ive lipids in yeast biology and disease pathogenesis. C, neoformans and C, albicans both secreted prostaglandins de novo or via conversion of exogenou s arachidonic acid. Treatment with cyclooxygenase inhibitors dramatically r educed the viability of the yeast and the production of prostaglandins, sug gesting that an essential cyclooxygenase like enzyme map be responsible for fungal prostaglandin production. A PGE series lipid was purified from both C, albicans and C, neoformans and mas biologically active on both fungal a nd mammalian cells. Fungal PGE, and synthetic PGE, enhanced the yeast-to-hy pha transition in C, albicans. Furthermore, in mammalian cells, fungal PGE, down-modulated chemokine production, tumor necrosis factor alpha productio n, and splenocyte proliferation while up-regulating interleukin 10 producti on. These are all activities previously documented for mammalian PGE,. Thus , eicosanoids are produced by pathogenic fungi, are critical for growth of the fungi, and can modulate host immune functions. The discovery that patho genic fungi produce and respond to immunomodulatory eicosanoids reveals a v irulence mechanism that has potentially great implications for understandin g the mechanisms of chronic fungal infection, immune deviation, and fungi a s disease cofactors.