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。是 健康的胃肠道微生物组的永久居民，主要作为 酵母形式。但当宿主免疫力受损时，传播性C.白色念珠菌感染可 死亡率很高。C.白色念珠菌是其 形态发生可塑性为了响应宿主的环境线索，这种真菌可以生长 作为酵母、假菌丝和菌丝形式。菌丝缺陷突变体 在系统性念珠菌病的动物模型中显示减弱的毒力。我们 长期目标是了解控制C.白色 形态发生我们实验室最近的研究表明， 由两个时间上相关联的阶段组成，即启动和维持。入会要求 Ras-cAMP-蛋白激酶A（PKA）通路，调节快速但暂时的 菌丝发育的Nrg 1转录抑制因子的消失。 维持需要Brg 1转录因子介导的启动子染色质 菌丝特异性基因对空气中营养限制或稳定化的反应的重塑 Ume 6转录激活因子在低氧和高碳酸血症下的表达。目标1将 对C.白念珠菌菌丝起始途径是系统性 感染我们将研究C.白色念珠菌细胞整合来自N- 乙酰葡糖胺、氨基酸和pH来控制菌丝起始程序。目标2将 使用突变筛选和遗传分析来揭示感知 低氧、高CO2和铁耗竭以维持系统性感染中菌丝伸长。 这一提议将获得对C. 在感染过程中控制菌丝发育，这在 了解其致病性。这些深入调查的结果将提供 新的洞察力的机制，管理菌丝启动和维持在一个 重要的真菌病原体，并将作为新的治疗基础 策略C。白色念珠菌此外，要检查的信号通路， 这种应用可能在不同的真菌病原体中是保守的。数据从这些 这些研究将提供对控制其他真菌毒力的信号通路的深入了解。

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.