Genotypic plasticity and parasex in Candida albicans

白色念珠菌的基因型可塑性和副性

• 批准号: 8849368
• 负责人: Richard John Bennett
• 金额: $ 20.31万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8849368
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adhesions; Affect; Aneuploidy; Antifungal Agents; Automobile Driving; Back; Biology; Candida; Candida albicans; Cell fusion; Cells; Chromosomes; Clinical; DNA; Diploidy; Disease; Drug resistance; Epigenetic Process; Event; Exhibits; Fungal Drug Resistance; Gastrointestinal tract structure; Genetic; Genome; Genomics; Genotype; Goals; HIV; Health; Human; Human body; Immune; Immunocompromised Host; In Vitro; Individual; Infection; Life; Life Style; Maintenance; Meiosis; Microbial Biofilms; Modeling; Mus; Mutation; Mycoses; Opportunistic Infections; Partner in relationship; Pathogenesis; Pathogenicity; Patients; Phenotype; Pheromone; Play; Ploidies; Population; Property; Recombinants; Reproduction; Resistance; Role; Sepsis; Sex Attractants; Signal Transduction; Site; Specificity; Stress; Systemic disease; Systemic infection; Testing; Tissues; Variant; Virulence; Work; antiretroviral therapy; asexual; chromosome 7 loss; chromosome loss; cohesion; fitness; fungus; in vivo; mortality; novel; oropharyngeal thrush; pathogen; programs; research study

DESCRIPTION (provided by applicant): The goal of this project is to address how the parasexual cycle of the fungus Candida albicans influences cell fitness and pathogenesis. This work is part of a long-range goal to understand the role of parasexuality in C. albicans colonization and disease in the mammalian host. C. albicans is the primary cause of oropharyngeal candidiasis (OPC), a condition that continues to afflict HIV-infected patients even in the era of antiretroviral therapy. C. albicans is also a prevalent cause of life-threatening systemic infections, particularly in nosocomial and immunocompromised populations. A defining feature of C. albicans biology is its ability to colonize and infect many sites throughout the human body. This remarkable ability is dependent on genetic and epigenetic mechanisms that act to promote phenotypic plasticity. Strains undergo switching between alternative cell states, and these transitions are essential to C. albicans's lifestyle both as a commensal and as an opportunistic pathogen. Morphologic and phenotypic changes influence virulence, tissue specificity, interactions with immune cells, and entry into the parasexual cycle. It is therefore essential to understand the mechanisms promoting phenotypic variation, and the consequences of such variation for infection of the host. A major goal of this proposal is to define the abilit of the parasexual cycle to generate novel C. albicans strains with the potential to promote pathogenesis. The parasexual cycle involves phenotypic switching to a mating-competent state, cell fusion to generate tetraploid cells, and concerted chromosome loss to form recombinant diploid or aneuploid strains. Exciting preliminary experiments establish that parasexuality can generate strains with increased virulence as well as increased resistance to environmental stress. A systematic analysis of parasex progeny will now be performed to identify isolates with stress-resistant phenotypes including resistance to antifungal drugs, as well as isolates that exhibit increased virulence. Genotyping of these isolates will determine the chromosomal changes that underlie these adaptive events. In particular, it is expected that the presence of specific aneuploid chromosomes will be associated with particular C. albicans phenotypes. A second goal is to identify the in vivo niche(s) that promote parasexual reproduction. Our studies indicate that particular regions of the gastrointestinal tract may preferentially support phenotypi switching and parasexual reproduction. This possibility will be directly tested by the experiments outlined here, including quantification of each of the steps of the parasexual cycle in vivo. Together, completion of the proposed experiments will therefore determine where parasexual reproduction occurs in vivo, and the consequences of this program for generating recombinant strains with increased pathogenicity.

描述（由申请人提供）：该项目的目的是解决真菌白色念珠菌的偏执循环如何影响细胞的适应性和发病机理。这项工作是了解寄生虫在哺乳动物宿主中寄生虫中的作用的远程目标的一部分。白色念珠菌是口咽念珠菌病（OPC）的主要原因，即使在抗逆转录病毒疗法的时代，这种疾病仍然会遭受HIV感染的患者。白色念珠菌也是威胁生命的全身感染的普遍原因，特别是在医院和免疫功能低下的人群中。白色念珠菌生物学的一个定义特征是它可以在整个人体中殖民和感染许多地点的能力。这种显着的能力取决于作用于促进表型可塑性的遗传和表观遗传机制。菌株在替代细胞状态之间进行切换，而这些转变对于白色念珠菌的生活方式既是共生的和机会性病原体都至关重要。形态和表型变化会影响毒力，组织特异性，与免疫细胞的相互作用以及进入寄生虫周期。因此，必须了解促进表型变异的机制，以及这种变异对宿主感染的后果。 该提案的一个主要目标是定义偏友周期的余地，以产生新型白色念珠菌菌株，并具有促进发病机理的潜力。偏执型循环涉及表型切换到竞争能力的状态，细胞融合以产生四倍体细胞，以及一致的染色体损失，形成重组二倍体或非整倍体菌株。令人兴奋的初步实验表明，偏执性可以产生毒力增加以及对环境压力的耐药性的增加。现在将对Parasex后代进行系统分析，以鉴定具有抗压力表型的分离株，包括对抗真菌药物的耐药性，以及表现出增加毒力的分离株。这些分离株的基因分型将决定这些适应性事件的基础的染色体变化。特别是，预计特定的非整倍体染色体的存在将与特定的白色念珠菌表型有关。第二个目标是确定促进偏执繁殖的体内生态裂市场。我们的研究表明，胃肠道的特定区域可能优先支持Phinotypi转换和寄生虫繁殖。此处概述的实验将直接测试这种可能性，包括对体内偏见循环的每个步骤进行定量。因此，所提出的实验的完成将确定在体内发生寄生虫繁殖的位置，以及该程序在致病性增加的情况下产生重组菌株的后果。