Control of Candida albicans Filamentous Growth and Virulence

白色念珠菌是人类主要的真菌病原体，可引起多种系统性和 粘膜感染。免疫功能受损的个人，如艾滋病患者、器官移植 接受者、接受化疗的癌症患者以及人工关节和假体的接受者 设备特别容易受到白色念珠菌的感染。众所周知，白色念珠菌会经历一种 从胚芽孢子(单轮发芽酵母细胞)到假菌丝和 菌丝(细长的细胞首尾相连)。经历这种转变的能力是 是致命性所必需的。我们的长期目标是确定白念珠菌 控制形态和毒力，以响应特定的寄主环境线索。为了 为了实现这一目标，我们已经确定了几个控制白色念珠菌的关键转录调控因子 丝状化以及白念珠菌丝状生长程序的表达。我们最近做了 显示了这些调节子之一UME6(编码一种新的细丝特异的 蛋白质)，足以确定白色念珠菌的形态，驱动菌丝延伸 并在系统性念珠菌病的小鼠模型中增强毒力；菌丝延长 已知细丝在各种与毒力相关的过程中发挥关键作用。第二个监管机构， NRG1作为细丝形成的关键抑制因子，在血清和 37℃(最强的成丝条件之一)。有几条证据表明Nrg1 和Ume6共同作用，控制丝状菌的生长和毒力，以响应各种 特定的主机环境提示和信号。为了解决这一假设，我们将执行 具体目标如下：1)确定Nrg1和Ume6控制丝状菌的机制 白念珠菌丝状生长程序的生长和表达，2)决定程度 其中Nrg1和Ume6在已知的各种调节和信号通路中发挥作用 对白念珠菌丝状生长和毒力很重要，3)决定特定宿主如何 环境线索控制Nrg1和Ume6的体外转录活性以及在 系统性念珠菌病小鼠体内模型的建立。各种遗传、分子、生化和 将采取基因组方法来实现这些目标。因为白色念珠菌能够 进行形态转换是毒力所必需的，这些研究也将显著 提高我们对真菌发病的潜在机制的理解，并最终 导致更有效的抗真菌疗法的发展

Candida albicans is the major human fungal pathogen responsible for a wide variety of systemic and mucosal infections. Immunocompromised individuals such as AIDS patients, organ transplant recipients, cancer patients undergoing chemotherapy and recipients of artificial joints and prosthetic devices are particularly susceptible to C. albicans infections. C. albicans is known to undergo a morphological transition from blastospores (single round budding yeast cells) to pseudohyphal and hyphal filaments (elongated cells attached end-to-end). The ability to undergo this transition is required for virulence. Our long-term goal is to determine the mechanisms by which C. albicans controls morphology and virulence in response to specific host environmental cues. In order to achieve this goal we have identified several key transcriptional regulators that control C. albicans filamentation as well as expression of the C. albicans filamentous growth program. We have recently shown that expression levels of one of these regulators, UME6 (encoding a novel filament-specific protein), are sufficient to determine C. albicans morphological form, drive hyphal filament extension and confer enhanced virulence in a mouse model of systemic candidiasis; extension of hyphal filaments is known to play a key role in a variety of virulence-related processes. A second regulator, Nrg1, functions as a key repressor of filamentation and is down-regulated in response to serum and 37¿C (one of the strongest filament-inducing conditions). Several lines of evidence suggest that Nrg1 and Ume6 function together to control filamentous growth and virulence in response to a variety of specific host environmetal cues and signals. In order to address this hypothesis we will carry out the following specific aims: 1) determine the mechanism by which Nrg1 and Ume6 control filamentous growth as well as expression of the C. albicans filamentous growth program, 2) determine the extent to which Nrg1 and Ume6 play a role in a variety of regulatory and signaling pathways known to be important for C. albicans filamentous growth and virulence, 3) determine how specific host environmental cues control the transcriptional activity of Nrg1 and Ume6 both in vitro as well as in a mouse model of systemic candidiasis in vivo. A variety of genetic, molecular, biochemical and genomic approaches will be taken to achieve these aims. Because the ability of C. albicans to undergo a morphological conversion is required for virulence, these studies will also significantly improve our understanding of the underlying mechanisms of fungal pathogenesis and eventually lead to the development of more effective antifungal therapies