Genetic Regulation of Heritable Switching in Candida albicans

白色念珠菌遗传转换的基因调控

基本信息

批准号：
10326376
负责人：
Richard John Bennett
金额：
$ 54.77万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-10 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10326376
关键词：
Address Adopted Affect Alleles Antifungal Agents Behavior Biology Candida albicans Cell Differentiation process Cells Clinical Color Diploidy Disease Environmental Risk Factor Epigenetic Process Event Exhibits Filament Frequencies Gastrointestinal tract structure Gene Dosage Generations Genes Genetic Genetic Polymorphism Genetic Recombination Genetic Transcription Genome Genomics Goals HIV Heritability Human body Immune Immune system Immunity In Vitro Individual Infection Laboratories Laboratory culture Lead Life Microbial Biofilms Modeling Molecular Morphology Mucous Membrane Mutagenesis Mutation Mycoses Nature Null Lymphocytes Open Reading Frames Oral cavity Outcome Oxidative Stress Pathogenesis Pathogenicity Phenotype Population Process Property Regulation Sepsis Sexual Reproduction Skin colonization Symbiosis Systemic disease Systemic infection Temperature Testing Tissues Virulence Woman base cell type clinically relevant experience experimental study fitness functional loss gastrointestinal gastrointestinal infection in vivo insight mouse model opportunistic pathogen oropharyngeal thrush trait transcription factor yeast infection

项目摘要

Project Summary Candida albicans is a commensal species that occupies diverse niches of the human body. It is also a prevalent opportunistic pathogen, being a frequent cause of debilitating mucosal infections and life-threatening systemic infections. In many cases, the commensal form is responsible for seeding systemic disease, which is often precipitated by a breakdown in host immunity. Despite its clinical importance, there remains limited understanding of commensal interactions between C. albicans and the host, or the fungal traits that influence invasion and disease during a disseminated infection. One of the most notable attributes of C. albicans is its ability to grow in different heritable states and morphological forms. The ability to transition between different phenotypic states can enable adaptation to host niches and modulate interactions with the immune system. Epigenetic mechanisms have been shown to regulate heritable switching between cell states, yet it is not known why only some clinical isolates undergo certain phenotypic switches, or how transitions between cell states determines outcomes in interactions with the host. We now propose a genetic mechanism underlies an important cell state transition in C. albicans that impacts both commensal and pathogenic behavior. C. albicans is a heterozygous diploid species and we made the unexpected observation that many clinical isolates are poised to undergo differentiation due to being functionally heterozygous for a key transcription factor. Furthermore, such heterozygous strains frequently lose the functional copy of the transcription factor gene both during laboratory culture and during infection of the host. The direct consequence of this transformative event is generation of a cell state that is hypercompetitive both in commensal and disseminated infection models. The goals of the current project are (1) to establish that changes in a master transcription factor gene direct a clinically relevant phenotypic switch, (2) to define whether the transcription factor gene represents a genomic hotspot for mutagenesis and/or recombination events, and (3) to examine cell state transition events during infection of the mammalian host, as well as the properties of different cell states that define fungal behavior in commensal and pathogenic models of infection. The proposed studies will provide new insights into how C. albicans adapts to different niches in the host, including an unexpected mechanism by which genetic polymorphisms and genomic plasticity combine to drive cell differentiation. These experiments will establish an important paradigm for C. albicans biology, as it is likely that other heterozygous loci are similarly primed for genetic events that drive adaptation in the host.

项目摘要白色念珠菌是一种占据人体各种细分市场的共生物种。这是也是一种普遍的机会性病原体，是粘膜感染和威胁生命的全身感染。在许多情况下，共生形式负责播种全身性疾病，通常是由于宿主免疫力破裂而引起的。尽管它的临床重要的是，对白色念珠菌与宿主或在传播感染过程中影响入侵和疾病的真菌特征。白色念珠菌最著名的属性之一是它在不同的遗传状态下成长的能力和形态形式。在不同表型状态之间过渡的能力可以实现适应托管壁ni，并调节与免疫系统的相互作用。表观遗传机制已显示显示细胞状态之间可遗传的切换，但尚不知道为什么只有一些临床分离株经历某些表型开关，或者细胞状态之间的过渡如何确定与主机互动的结果。现在，我们提出的一种遗传机制是白色念珠菌中重要的细胞状态过渡的基础这影响了共生和致病行为。白色念珠菌是一种杂合二倍体物种我们表明了许多临床分离株有望进行的意外观察由于在功能上是关键转录因子的功能杂合引起的分化。此外，这样的杂合菌株经常失去转录因子基因的功能副本，两者都在实验室文化和宿主感染期间。这个变革事件的直接后果是在共生和传播感染模型中产生过度竞争的细胞状态。当前项目的目标是（1）确定主转录因子的变化基因指导临床上相关的表型转换，（2）定义转录因子基因是否定义代表用于诱变和/或重组事件的基因组热点，（3）检查细胞哺乳动物宿主感染期间的状态过渡事件以及不同细胞的特性指出在感染的共生和致病模型中定义真菌行为。拟议的研究将提供有关白色念珠菌如何适应不同壁ni的新见解宿主，包括一种意外的机制，遗传多态性和基因组可塑性结合驱动细胞分化。这些实验将为C建立重要的范式。白色唱片生物学，因为其他杂合基因座可能同样是针对遗传事件的主机中的驱动器改编。