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，负责各种系统性和粘膜感染。艾滋病患者，器官移植受者，接受化学疗法的癌症患者，人造关节和人造装置的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的影响。已知白色念珠菌会经历从酵母（单个，圆形萌芽细胞）到伪植物和菌丝丝（端到端附着的细胞）的形态过渡，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促进对宿主环境线索的响应。尽管伪植物和菌丝形式之间的表型差异已得到充分表征，但对决定每种形态的生长或每个形态在毒力中扮演的特定作用的调节机制知之甚少。为了解决这些问题，我们最近产生了一种可以在遗传上操纵的白色念珠菌菌株，可以在体外非诱导的菌丝形态中完全生长在菌丝形态中。我们还发现，这种菌株能够推动增加菌丝形成并促进全身性念珠菌病的小鼠模型中的毒力。我们的菌株是通过将新型细丝特异性转录调节因子的一个等位基因置于可调节启动子的控制下的。有趣的是，虽然高级UME6表达驱动了完全菌丝的生长，但中级UME6水平在很大程度上指定了假植物群，这表明UME6表达水平足以以剂量依赖性的方式确定白色念珠菌形态。初步研究表明，随着UME6水平的上升，诱导的丝特异性转录本的数量以及它们的诱导水平都在增加。我们的假设是，受宿主环境提示影响的UME6水平通过控制丝状特异性转录物的重叠集的表达水平来确定白色念珠菌的形态和毒力。为了解决这一假设，我们计划执行以下三个具体目的：1）确定上游宿主环境信号和已知的C. bilmats丝状生长调节循环控制ume6，2）2）2）2）确定为UME6剂量表达的白色念珠菌基因的转录性概况，指定了ume6剂量的特定方式，并促进了特定的原理，并促进了特定的机制。对于UME6水平确定白色念珠菌形态并促进毒力的能力很重要。最终，这些研究将显着提高我们对真菌病原体如何指定形态和促进宿主环境中的毒力的理解，并将提供可能导致新颖和更有效的抗真菌策略发展的信息。 公共卫生相关性：白色念珠菌是引起酵母菌感染并杀死免疫系统弱的人的主要酵母。该研究建议旨在更好地了解白色念珠菌如何作为一种有效的病原体发挥作用。最终，这些研究应提供信息，从而开发出更有效的酵母菌感染治疗方法。