Signal sensing, hyphal development and pathognesis of Candida albicans

项目摘要 白色念珠菌是人类最常见的真菌病原体之一。一 C.的关键毒力属性。白色念珠菌的主要特征是其形态发生可塑性。响应于 宿主环境提示，这种真菌可以作为酵母，假菌丝和菌丝生长 forms.在菌丝形成中有缺陷的突变体显示减弱的毒力， 系统性念珠菌病的动物模型。我们的长期目标是了解 控制C的途径白色念珠菌形态发生我们实验室的研究表明， 菌丝发育包括两个时间上相互联系的阶段，起始和 上维护起始需要Ras-cAMP-蛋白激酶A（PKA）途径， 调节Nrg 1转录抑制因子的快速但暂时的消失， 菌丝发育维持需要Brg 1转录因子介导的 营养限制对菌丝特异性基因启动子染色质重塑的影响 或在缺氧下稳定Ume 6转录激活因子， 高碳酸血症我们已经发现了N-乙酰葡糖胺（GlcNAc）的保守传感器， 二氧化碳和缺氧与菌丝的发育有关。在目前的提案中，我们将 通过以下目标扩展这些研究：目标1.调查Nrg 1下降- 菌丝起始过程中的调控。目标二。检查菌丝的信号通路 巨噬细胞内的形态发生。目标3。识别转录程序 低氧和生理性CO2。这项提议将从分子上深入了解宿主 信号由C感知。白色念珠菌控制菌丝的发展过程中感染， 对了解其致病性至关重要这些深入研究的结果 这些研究将对控制菌丝起始的机制提供新的认识 和维护在一个重要的真菌病原体，并将作为基础， 针对C.白色念珠菌此外， 在本申请中被检测的病原体可能在不同的真菌病原体中保守。 这些研究的数据将提供对控制毒力的信号通路的深入了解 在其他真菌中。

PROJECT SUMMARY Candida albicans is one of the most frequently isolated fungal pathogens of humans. A critical virulence attribute of C. albicans is its morphogenetic plasticity. In response to host environmental cues, this fungus can grow as yeast, pseudohyphal, and hyphal forms. Mutants that are defective in hyphal formation display attenuated virulence in animal models of systemic candidiasis. Our long-term goal is to understand the signaling pathways that govern C. albicans morphogenesis. Studies from our laboratory show that hyphal development consists of two temporally linked phases, initiation and maintenance. Initiation requires the Ras-cAMP-protein kinase A (PKA) pathway that regulates the rapid but temporary disappearance of the Nrg1 transcriptional repressor of hyphal development. Maintenance requires the Brg1 transcription factor-mediated promoter chromatin remodeling of hypha-specific genes in response to nutrient limitation in air or stabilization of the Ume6 transcriptional activator under hypoxia and hypercapnia. We have uncovered conserved sensors for N-actylglucosamine (GlcNAc), CO2, and hypoxia that are linked to hyphal development. In the current proposal, we will extend these studies through the following aims: Aim 1. Investigate Nrg1 down- regulation during hyphal initiation. Aim 2. Examine signaling pathways for hyphal morphogenesis inside macrophage. Aim 3. Identify transcriptional programs under hypoxia and physiological CO2. This proposal will gain molecular insights into how host signals are sensed by C. albicans to control hyphal development during infection, which is critically important in understanding its pathogenicity. The results of these in-depth investigations will provide new insight into the mechanisms that govern hyphal initiation and maintenance in an important fungal pathogen, and will serve as the foundation for novel therapeutic strategies against C. albicans. Furthermore, the signaling pathways to be examined in this application are likely conserved among diverse fungal pathogens. Data from these studies will provide insight into signaling pathways that govern virulence in other fungi.