Biology of Fungal Melanin

黑色素与许多重要的生物过程有关，但它们仍然是个谜 聚合物对于包括新型隐球菌在内的几种机会致病真菌，黑色素 合成与毒力有关。C.新生儿是脑膜脑炎的主要原因， 艾滋病患者。黑色素合成已被证明发生在C。新生儿 感染黑色素促进黑色素生成的机制尚不清楚，但可能 涉及干扰宿主效应机制。除了它们在微生物中的重要性外， 发病机制，有证据表明，黑色素降低某些抗真菌药物的疗效，这意味着 这种色素可以作为抗微生物药物开发的目标。事实上，有证据表明， 干扰黑色素聚合的化合物在小鼠实验中是有治疗作用的 感染黑色素是免疫原性的，可以引发抗体，保护免受实验C。 新生儿感染。黑色素抗体与黑色素细胞结合后导致细胞生长停滞 这表明了抗真菌抗体作用的新机制。此应用程序的目标是 更好地定义黑色素有助于毒力的机制，以研究黑色素的作用。 抗体对黑色素和漆酶在宿主保护中的反应以及与黑色素和漆酶相关的生物活性， 通过使用标记的底物探测黑色素的结构，提出了三个目标：1） 建立黑色素促进C.体内新生儿，2） 建立抗C.黑色素和漆酶， 抗体作用机制; 3）研究C.新生黑色素使用 生物合成掺入的底物。预计这里提议的工作将提供 黑色素生物学的重要见解，并在这样做突出了新的战略， 抗微生物药物开发。

Melanins are implicated in a variety of important biological processes yet they remain enigmatic polymers. For several oopportunistic pathogenic fungi including Cryptococcus neoformans, melanin synthesis is associated with virulence. C. neoformans is a major cause of meningoencephalitis in patients with AIDS. Melanin synthesis has been demonstrated to occur in C. neoformans during infection. The mechanism by which melanin contributes to virulene is poorly understood but may involve interference with host effector mechanisms. Apart from their importance in microbial pathogenesis, there is evidence that melanins reduce the efficacy of certain antifungal drugs implying that this pigment can be targeted for antimicrobial drug development. In fact, there is evidence that compounds which interfere with melanin polymerization can be therapeutic in murine experimental infection. Melanin is immunogenic and can elicit antibodies that protect against experimental C. neoformans infection. Antibodies to melanin cause cell growth arrest after binding to melanized cells indicating a novel mechanism of antibody action against fungi. The goals of this application are to better define the mechanisms by which melanin contributes to virulence, to investigate the role of antibody responses to melanin and laccase in host protection and correlate biological activity with structure by probing the structure of melanin using labeled substrates. Three aims are proposed: 1) to establish the mechanism by which melanin promotes the virulence of C. neoformans in vivo, 2) to establish the protective efficacy of antibody to C. neoformans melanin and laccase and the mechanism of antibody action, 3) to investigate the structure of C. neoformans melanin using biosynthetically incorporated substrates. It is anticipated that the work proposed here will provide important insights into the biology of melanin and in doing so highlight novel strategies for antimicrobial drug development.