Role of Oxylipins in Cryptococcal Pathogenesis

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DESCRIPTION (provided by applicant): Cryptococcus neoformans is an opportunistic pathogen. It is a wood rot fungus that is inhaled from the environment (usually early in life) and very likely persists at low levels in the body until a reactivating event occurs (such as AIDS). The vast majority of life-threatening Cryptococcus infections are reactivation diseases. However, the mechanism by which low numbers of fungal organisms can persist in the face of an adaptive immune response is unknown. Recently, our laboratory identified that Cryptococcus and other pathogenic fungi can produce prostaglandins and leukotrienes. These are bioactive lipids derived from the fatty acid arachidonic acid and collectively belong to a larger class of bioactive lipids known as oxylipins (oxygenated fatty acid derivatives). Prostaglandins and leukotrienes are also produced by the host and are well-described modulators of innate and adaptive immune responses. The fact that both the host and fungus can produce similar signal molecules suggests a novel mechanism for low level fungal persistence. The hypothesis of this proposal is that production of oxylipins by both fungi and host modulates the microbiology of the fungus and the host-pathogen interaction in favor of chronic infection or persistence. The Specific Aims are (1) to determine the effect of exogenous 18 and 20 carbon fatty acids, in the presence or absence of polyphenols, on modulating the biology of Cryptococcus neoformans (growth, melanization, capsule, cAMP production, phase transformation, Mfod activation, antifungal susceptibility); (2) to determine the role of cryptococcal laccase (CNLAC1) in fatty acid utilization and oxylipin production; (3) to determine the role of the fungal oxylipin CnPGEx in cryptococcal biology and pathogenesis; (4) to determine the role of host PGE2 and other prostaglandins in cryptococcal biology and host immunity