Role of Oxylipins in Cryptococcal Pathogenesis

描述（由申请人提供）：新型隐球菌是一种机会致病菌。这是一种从环境中吸入的木腐菌（通常在生命早期），并且很可能在体内保持低水平，直到重新激活事件发生（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，面对适应性免疫反应，低数量真菌有机体能够持续存在的机制尚不清楚。最近，我们实验室发现隐球菌和其他病原真菌可以产生前列腺素和白三烯。这些是从脂肪酸花生四烯酸衍生出来的生物活性脂质，它们共同属于更大的一类生物活性脂质，即氧合脂肪酸衍生物。前列腺素和白三烯也由宿主产生，是先天和适应性免疫反应的良好调节剂。事实上，宿主和真菌都可以产生相似的信号分子，这表明真菌的低水平持久性存在一种新的机制。这一提议的假设是，真菌和宿主产生的氧化脂素调节了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18和20碳脂肪酸在存在或不存在多酚的情况下对调节新型隐球菌生物学（生长、黑化、胶囊、cAMP生成、相变、Mfod激活、抗真菌敏感性）的影响；(2)确定隐球菌漆酶（CNLAC1）在脂肪酸利用和氧化脂质的作用；(3)确定真菌氧脂素CnPGEx在隐球菌生物学和发病机制中的作用；(4)确定宿主PGE2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