Role of Oxylipins in Cryptococcal Pathogenesis

描述(申请人提供)：新生隐球菌是一种机会性病原体。它是一种木腐菌，从环境中吸入(通常是在生命早期)，很可能在体内以低水平持续存在，直到发生重新激活的事件(如艾滋病)。绝大多数威胁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，低数量的真菌生物能够持续存在的机制尚不清楚。最近，我们实验室鉴定出隐球菌等病原真菌可产生前列腺素和白三烯。这些都是源于脂肪酸花生四烯酸的生物活性脂类，共同属于一大类生物活性脂类，称为氧脂素(含氧脂肪酸衍生物)。前列腺素和白三烯也是由宿主产生的，它们是天然和获得性免疫反应的调节器。寄主和真菌都可以产生相似的信号分子，这一事实表明了一种新的低水平真菌持续存在的机制。这一建议的假设是，真菌和宿主产生的氧磷脂调节真菌的微生物学和宿主与病原体的相互作用，有利于慢性感染或持久性。其具体目的是(1)确定外源18和20碳脂肪酸在有或没有多酚的情况下对新生隐球菌生物学(生长、黑化、被膜、cAMP产生、相变、Mfod激活、抗真菌敏感性)的调节作用；(2)确定隐球菌漆酶(CNLAC1)在脂肪酸利用和氧脂产生中的作用；(3)确定真菌氧脂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