Biology of Fungal Melanin

描述（由申请人提供）：黑色素色素与大多数机会性真菌病原体的毒力有关，这些病原体在免疫功能低下患者（包括艾滋病患者）中引起危及生命的疾病。黑色素通过降低对宿主免疫机制的易感性和颠覆免疫反应的组合，增加宿主微生物的适应性，从而促进毒力。此外，黑色素降低了真菌对多烯和棘白菌素类抗真菌药物的敏感性，因此是获得性耐药的重要组成部分。鉴于黑色素在毒力和耐药性中的重要性，控制黑色素合成和细胞壁组装的机制是药物发现的潜在重要目标。最近，细胞壁黑色素化与暴露于伽马辐射后真菌细胞生长效应的增加有关，这表明这种神秘的色素在能量转导中起着新的作用。本应用程序旨在通过剖析人类致病真菌新隐球菌的黑色素化过程，继续我们对真菌黑色素生物学的研究。这种生物是艾滋病患者的主要病原体，并为黑色素生物学的研究提供了一个独特的系统，因为它只有在外源底物存在的情况下才会变黑，并且具有广泛的遗传工具箱。黑化过程中对外源底物的需求为利用同位素代谢标记和核磁共振波谱技术研究黑色素结构提供了独特的机会。本研究计划的目标是进一步了解致病性真菌中的黑色素生物学、功能和结构。提出了三个具体的目标：1)确定新生黑素化与囊泡相关；2)建立细胞外囊泡、黑素体与毒力的关系；3)研究新生隐球菌黑色素生物合成的分子事件。公共卫生相关性：该项目与美国国立卫生研究院的使命相关，因为黑色素的研究可以导致治疗真菌疾病的新疗法。此外，该研究也与黑色素瘤等人类色素组织疾病有关。在这方面，作为该研究项目的一部分，一种针对真菌黑色素的单克隆抗体已经在黑色素瘤治疗的临床评估中。

DESCRIPTION (provided by applicant): Melanin pigments have been associated with virulence for most opportunistic fungal pathogens that cause life-threatening diseases in immunocompromised patients, including those with AIDS. Melanins contribute to virulence by increasing the fitness of the microbe in the host through a combination of reduced susceptibility to host immune mechanisms and subversion of the immune response. In addition, melanins reduce the susceptibility of fungi to polyene and echinocandin type antifungal agents and thus represent an important component of acquired drug resistance. Given the importance of melanin in virulence and drug resistance, the mechanisms that govern melanin synthesis and assembly in cell walls are potentially important targets for drug discovery. Recently, cell wall melanization was associated with increased fungal cell growth effects after exposure to gamma irradiation suggesting a novel role for this enigmatic pigment in energy transduction. This application proposes to continue our studies of the biology of fungal melanin by dissecting the process of melanization in the human pathogenic fungus Cryptococcus neoformans. This organism is a major pathogen for patients with AIDS and provides a unique system for the study of melanin biology because it melanizes only in the presence of an exogenous substrate and has an extensive genetic toolbox. The requirement for exogenous substrates in melanization provides a unique opportunity for studying melanin structure by using isotopic metabolic labeling and nuclear magnetic resonance spectroscopy. The goal of this research program is to further our understanding of melanin biology, function, and structure in pathogenic fungi. Three specific aims are proposed: 1) To establish that melanization in C. neoformans is vesicle-associated; 2) To establish the relationship between extracellular vesicles, melanosomes, and virulence; 3) To investigate the molecular events of C. neoformans melanin biosynthesis. PUBLIC HEALTH RELEVANCE: This project is relevant to the mission of the NIH because studies of melanin can lead to new therapies for the treatment of fungal diseases. Furthermore, the research is also relevant to human diseases of pigmented tissues such as melanoma. In this regard, a monoclonal antibody to fungal melanin made as part of this research program is already in clinical evaluation for the therapy of melanoma.