Role of Oxylipins in Cryptococcal Pathogenesis

性状（由申请方提供）：新型隐球菌是一种机会致病菌。它是一种木材腐烂真菌，从环境中吸入（通常在生命早期），并且很可能在体内以低水平持续存在，直到发生重新激活事件（如艾滋病）。绝大多数危及生命的隐球菌感染是再激活疾病。然而，在适应性免疫反应面前，少量真菌生物体可以持续存在的机制尚不清楚。本实验室最近发现隐球菌等病原真菌能产生白藜芦醇和白三烯。这些是衍生自脂肪酸花生四烯酸的生物活性脂质，并且共同属于被称为氧脂素（氧化脂肪酸衍生物）的较大类别的生物活性脂质。前列腺素和白三烯也由宿主产生，并且是先天性和适应性免疫应答的充分描述的调节剂。宿主和真菌都能产生相似的信号分子，这一事实表明了低水平真菌持久性的一种新机制。这一提议的假设是，真菌和宿主产生的氧化脂质调节真菌的微生物学和宿主-病原体相互作用，有利于慢性感染或持久性。具体目的是（1）确定外源性18和20碳脂肪酸在存在或不存在多酚的情况下对新型隐球菌生物学的调节作用（2）隐球菌漆酶（CNLAC 1）在脂肪酸利用和氧脂素合成中的作用;（3）确定真菌氧化脂素CnPGEx在隐球菌生物学和发病机制中的作用;（4）确定宿主PGE 2和其他前列腺素在隐球菌生物学和宿主免疫中的作用

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