Genetic Regulation of Heritable Switching in Candida albicans

白色念珠菌遗传转换的基因调控

• 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
• 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

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 白色念珠菌是一种寄生菌，占据人体的不同小生境。是 也是一种普遍的机会致病菌，是使人衰弱的粘膜感染的常见原因， 危及生命的全身感染在许多情况下，种子形式负责播种， 系统性疾病，通常由宿主免疫力的破坏引起。尽管其临床 重要的是，仍然有有限的理解之间的相互作用C。白色念珠菌和 宿主，或在传播感染期间影响入侵和疾病的真菌性状。 C.白色念珠菌是其在不同的遗传状态下生长的能力 和形态学形式。在不同表型状态之间转换的能力可以使 适应宿主生态位并调节与免疫系统的相互作用。表观遗传机制 已被证明可以调节细胞状态之间的遗传转换，但尚不清楚为什么只有一些 临床分离物经历某些表型转换，或者细胞状态之间的转换如何决定 与宿主互动的结果。 我们现在提出了一个遗传机制的基础上一个重要的细胞状态转换在C。白色 既影响行为也影响致病行为。C.白色念珠菌是杂合子二倍体种 我们意外地观察到许多临床分离株 由于对于关键转录因子是功能性杂合的，因此分化。此外，这种 杂合菌株经常丢失转录因子基因的功能拷贝， 实验室培养和宿主感染期间。这一变革性事件的直接后果是 产生的细胞状态，是超竞争性的，在寄生虫和传播感染模型。 本研究的目的是：（1）确定转录因子的变化 基因指导临床相关的表型转换，（2）确定转录因子基因是否 代表诱变和/或重组事件的基因组热点，和（3）检查细胞 哺乳动物宿主感染过程中的状态转换事件，以及不同细胞的性质 定义真菌在真菌感染和致病模型中的行为。 这些研究将为C.白色念珠菌适应不同的生态位， 宿主，包括一个意想不到的机制，遗传多态性和基因组可塑性 联合收割机来驱动细胞分化。这些实验将为C. 白念珠菌生物学，因为其他杂合基因座很可能类似地引发遗传事件， 主机中的驱动器适配。