Signal sensing, hyphal development and pathogenesis of Candida albicans

白色念珠菌是人类最常见的真菌病原体之一。它是 健康的胃肠道微生物群的永久居民，主要以 酵母形态。但当宿主免疫力受损时，播散性白色念珠菌感染可能 发生时死亡率很高。白念珠菌的一个关键毒力属性是它的 形态发生可塑性。作为对宿主环境信号的响应，这种真菌可以生长 以酵母、假菌丝和菌丝形式存在。菌丝有缺陷的突变体 在系统性念珠菌病的动物模型中，队形显示毒力减弱。我们的 长期目标是了解控制白色念珠菌的信号通路。 形态发生。我们实验室最近的研究表明，菌丝发育 由启动和维护两个时间上相关联的阶段组成。入门需要 Ras-cAMP-蛋白激酶A(PKA)通路调节快速但暂时的 菌丝发育的Nrg1转录抑制因子的消失。 维持需要BRG1转录因子介导的启动子染色质 菌丝特异性基因重塑对空气中营养限制或稳定剂的响应 Ume6转录激活子在低氧和高二氧化碳条件下的表达。目标1将 描述系统性白念珠菌菌丝起始途径的特征 感染。我们将研究白色念珠菌细胞如何整合来自N-的信号 控制菌丝起始程序的乙酰氨基葡萄糖、氨基酸和pH。目标2将 使用突变筛选和基因分析来发现感知信号通路 在系统性感染中，低氧、高二氧化碳和铁的消耗可以维持菌丝的伸长。 这一提议将从分子上深入了解寄主信号是如何被C. 白念珠菌在感染过程中控制菌丝发育，这在 了解它的致病性。这些深入调查的结果将提供 菌丝起始和维持机制的新见解 重要的真菌病原体，并将作为新的治疗方法的基础 抗击白色念珠菌的策略。此外，要研究的信号通路 这一应用可能在不同的真菌病原体中保守。来自这些网站的数据 研究将提供对控制其他真菌毒力的信号通路的洞察。

Candida albicans is one of the most frequently isolated fungal pathogens of humans. It is a permanent resident of the healthy gastrointestinal microbiome, existing mostly as the yeast form. But when host immunity is impaired, disseminated C. albicans infections can occur with a high mortality rate. 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. Recent 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. Aim 1 will characterize the C. albicans hyphal initiation pathways that are essential for systemic infection. We will study how C. albicans cells integrate signals from N- acetylglucosamine, amino acids and pH to control hyphal initiation programs. Aim 2 will use mutant screens and genetic analysis to uncover signaling pathways that sense hypoxia, high CO2, and iron depletion to sustain hyphal elongation in systemic infection. 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.