Determination of morphology and virulence in Candida albicans

白色念珠菌形态和毒力的测定

• 批准号: 8071573
• 负责人: DAVID KADOSH
• 金额: $ 32.94万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8071573
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adhesions; Affect; Agar; Alleles; Antifungal Agents; Antifungal Therapy; Automobile Driving; Cancer Patient; Candida albicans; Cells; Complementary DNA; Cues; Cytolysis; DNA Microarray Chip; Development; Disseminated candidiasis; Environment; Filament; Gene Expression; Gene Targeting; Genes; Genome; Goals; Growth; Human; Hyphae; Immune system; Immunocompromised Host; In Vitro; Indium; Individual; Infection; Joints; Lead; Microarray Analysis; Microbial Biofilms; Modeling; Morphology; Oral mucous membrane structure; Organ Transplantation; Pathogenesis; Patients; Peptide Hydrolases; Play; Population; Positioning Attribute; Process; Property; Prosthesis; Public Health; Regulatory Pathway; Research Proposals; Role; Signal Pathway; Signal Transduction; Specific qualifier value; Testing; Tissue Engineering; Tissues; To specify; Transcript; Transplant Recipients; Virulence; Yeasts; base; chemotherapy; chromatin immunoprecipitation; dosage; effective therapy; extracellular; fungus; improved; in vivo; killings; macrophage; mouse model; mutant; neutrophil; novel; pathogen; promoter; public health relevance; research study; response

DESCRIPTION (provided by applicant): Candida albicans, the major human fungal pathogen, is responsible for a wide variety of systemic and mucosal infections. AIDS patients, organ transplant recipients, cancer patients undergoing chemotherapy, recipients of artificial joints and prosthetic devices and other immunocompromised individuals are particularly susceptible to C. albicans infections. C. albicans is known to undergo a morphological transition from yeast (single, round budding cells) to pseudohyphal and hyphal filaments (elongated cells attached end-to-end) which is required for virulence. Our long-term goal is to determine how C. albicans controls morphology and promotes virulence in response to host environmental cues. Although phenotypic differences between pseudohyphal and hyphal forms have been well-characterized, very little is known about the regulatory mechanisms that determine growth in each morphology or the specific role that each morphology plays in virulence. In order to address these questions, we have recently generated a C. albicans strain that can be genetically manipulated to grow completely in the hyphal morphology under non-filament-inducing conditions in vitro. We have also found that this strain is capable of driving increased hyphal formation and promoting virulence in a mouse model of systemic candidiasis. Our strain was generated by placing one allele of a novel filament-specific transcriptional regulator of C. albicans hyphal extension and virulence, UME6, under the control of a regulatable promoter. Interestingly, while high-level UME6 expression drives complete hyphal growth, intermediate UME6 levels specify a largely pseudohyphal population, indicating that UME6 expression levels are sufficient to determine C. albicans morphology in a dosage-dependent manner. Preliminary studies show an increase in both the number of filament-specific transcripts induced as well as their level of induction as UME6 levels rise. Our hypothesis is that UME6 levels, which are affected by host environmental cues, determine C. albicans morphology and virulence by controlling the expression level of overlapping sets of filament-specific transcripts. In order to address this hypothesis we plan to carry out the following three specific aims: 1) determine how upstream host environmental signals and known C. albicans filamentous growth regulatory circuits control the expression of UME6, 2) determine the transcriptional profile of C. albicans genes expressed as UME6 dosage specifies pseudohyphal and hyphal morphologies and promotes virulence during infection, 3) identify specific downstream mechanisms that are important for the ability of UME6 levels to determine C. albicans morphology and promote virulence. Ultimately, these studies will significantly improve our understanding of how fungal pathogens specify morphology and promote virulence in the host environment and will provide information that could lead to the development of novel and more effective antifungal strategies. PUBLIC HEALTH RELEVANCE: Candida albicans is the major yeast that causes yeast infections and also kills people with weakened immune systems. This research proposal aims to gain a better understanding of how Candida albicans is able to function as such an effective pathogen. Ultimately, these studies should provide information leading to the development of more effective treatments for yeast infections.

描述（由申请人提供）：白色念珠菌是主要的人类真菌病原体，可引起多种全身和粘膜感染。艾滋病患者、器官移植接受者、接受化疗的癌症患者、人工关节和假肢装置接受者以及其他免疫功能低下的个体特别容易受到白色念珠菌感染。已知白色念珠菌会经历从酵母（单个圆形出芽细胞）到假菌丝和菌丝（首尾相连的细长细胞）的形态转变，这是毒力所必需的。我们的长期目标是确定白色念珠菌如何控制形态并增强毒力以响应宿主环境线索。尽管假菌丝和菌丝形式之间的表型差异已得到充分表征，但对于决定每种形态生长的调节机制或每种形态在毒力中发挥的具体作用，人们知之甚少。为了解决这些问题，我们最近产生了一种白色念珠菌菌株，可以通过基因操作在体外非丝状诱导条件下完全以菌丝形态生长。我们还发现，该菌株能够在系统性念珠菌病小鼠模型中促进菌丝形成并增强毒力。我们的菌株是通过将白色念珠菌菌丝延伸和毒力的新型丝状特异性转录调节因子 UME6 的一个等位基因置于可调节启动子的控制下而产生的。有趣的是，虽然高水平的 UME6 表达驱动完整的菌丝生长，但中等 UME6 水平指定了大部分假菌丝群体，表明 UME6 表达水平足以以剂量依赖性方式确定白色念珠菌的形态。初步研究表明，随着 UME6 水平的升高，诱导的细丝特异性转录本的数量及其诱导水平都会增加。我们的假设是，受宿主环境因素影响的 UME6 水平通过控制丝状特异性转录物重叠组的表达水平来决定白色念珠菌的形态和毒力。为了解决这一假设，我们计划实现以下三个具体目标：1）确定上游宿主环境信号和已知的白色念珠菌丝状生长调节电路如何控制UME6的表达，2）确定表达为UME6剂量的白色念珠菌基因的转录谱，指定假菌丝和菌丝形态并促进感染期间的毒力，3）确定特定的下游机制 这对于 UME6 水平确定白色念珠菌形态和促进毒力的能力非常重要。最终，这些研究将显着提高我们对真菌病原体如何确定形态并促进宿主环境中毒力的理解，并将提供可能导致开发新颖且更有效的抗真菌策略的信息。 公共卫生相关性：白色念珠菌是引起酵母菌感染的主要酵母菌，也会杀死免疫系统较弱的人。该研究计划旨在更好地了解白色念珠菌如何能够发挥如此有效的病原体作用。最终，这些研究应该提供有助于开发更有效的酵母菌感染治疗方法的信息。