Signal sensing, hyphal development and pathognesis of Candida albicans

项目总结 白色念珠菌是人类最常见的真菌病原体之一。一个 白念珠菌的关键毒力属性是其形态发生可塑性。作为对.的回应 寄主环境提示，这种真菌可以以酵母、假菌丝和菌丝的形式生长 表格。菌丝形成缺陷的突变体显示出毒力减弱 系统性念珠菌病的动物模型。我们的长期目标是理解信号 控制白念珠菌形态发生的途径。我们实验室的研究表明 菌丝发育由两个时间上相连的阶段组成，即起始阶段和 维修。启动需要RAS-cAMP-蛋白激酶A(PKA)途径， 调节Nrg1转录抑制子的快速但暂时的消失 菌丝发育。维持需要BRG1转录因子介导 菌丝特异性基因启动子染色质重塑对营养限制的响应 在空气中或Ume6转录激活子在低氧和 高碳酸血症。我们发现了N-乙酰氨基葡萄糖(GlcNAc)的保守传感器， 二氧化碳和低氧与菌丝发育有关。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Nrg1- 菌丝起始过程中的调控。目标2.检查菌丝的信号通路 巨噬细胞内的形态发生。目标3.确定以下条件下的转录程序 低氧和生理性二氧化碳。这项提案将从分子上深入了解宿主 白念珠菌在感染过程中感知信号来控制菌丝的发育，这 对了解其致病性至关重要。这些深入研究的结果 研究将为控制菌丝起始的机制提供新的见解 和维持一种重要的真菌病原体，并将作为基础 针对白色念珠菌的新治疗策略。此外，信号转导途径 可能在不同的真菌病原体中保守。 来自这些研究的数据将提供对控制毒力的信号通路的洞察 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.