Phenotypic Plasticity and Sexual Reproduction in Candida tropicalis Pathogenesis

热带假丝酵母发病机制的表型可塑性和有性生殖

• 批准号: 8672625
• 负责人: Allison Marly Porman Swain
• 金额: $ 0.44万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-16 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8672625
• 关键词: Address; Affect; Animal Model; Antifungal Agents; Biology; Candida; Candida albicans; Candida tropicalis; Cells; Denture Stomatitis; Disease; Disseminated candidiasis; Environment; Gene Expression; Generations; Genetic; Genetic Recombination; Genetic Variation; Growth; Health; High Prevalence; Human; Immune system; Infection; Inflammation; Knowledge; Life; Life Cycle Stages; Life Style; Mating Types; Modeling; Morbidity - disease rate; Mycoses; Organism; Partner in relationship; Pathogenesis; Patients; Phenotype; Play; Ploidies; Population; Process; Recombinants; Regulation; Relative (related person); Reproduction; Research; Role; Sepsis; Specificity; Systemic infection; Tissues; Transcriptional Regulation; Virulence; Virulent; Yeasts; asexual; base; fitness; fungus; mortality; novel; pathogen; programs; research study; sex

DESCRIPTION (provided by applicant): Candida species include fungal species that exist as natural commensals, but can become pathogenic if the host immune system has been compromised. Although Candida albicans is the most common fungal pathogen, infections due to Candida tropicalis have increased worldwide, establishing it as an emerging pathogen. Despite the importance of C. tropicalis infections and the high mortality rate associated with this species, little is known about its lifecycle and how it impacts disease. Significantly, my preliminary experiments have identified a novel form of phenotypic switching in C. tropicalis and that this switch regulates a cryptic program of sexual reproduction in this species. Based on these findings, this proposal will address how these newly discovered aspects of C. tropicalis impact its pathogenesis. As phenotypic plasticity can provide fitness advantages by allowing an organism to rapidly adapt to changing environments, it is important to study the phenotypic states of C. tropicalis and how they contribute to this species' ability to colonize and infect the mammalian host. The experiments outlined in Aim 1 will therefore examine the regulation of the white and opaque phenotypic states of C. tropicalis, and their differences in virulence and tissue specificity. For the second aim of this proposal, I will address how the mating cycle is completed in C. tropicalis, and how mating affects the virulence of this species. The experiments outlined in Aim 2.1 will elucidate the mechanism of ploidy reduction in the sexual cycle of C. tropicalis, as genetic variation that can result from the generation of recombinant progeny has implications for the organism's ability to survive and adapt to stressful environments. Thus, determining a mechanism for ploidy reduction and recombination will be important for analyzing the ability of this species to generate genetic diversity within a mainly clonal, but sexually reproducing, population. Moreover, information contained at the mating-type-like locus (MTL) is expected to influence the virulence of Candida species, as C. albicans strains that are MTLa/α have been shown to be more virulent than their homozygous a/a or α/α counterparts. To determine if the information at the sex locus also alters the virulence of C. tropicalis isolates, Aim 2.2 will examine the competitive fitness of MTLa/a, α/α, and a/α isolates in colonizing the host. These experiments will enable a more thorough understanding of how information at the sex-determining locus contributes to the ability of C. tropicalis isolates to colonize and infect the mammalian host. Overall, my discovery of switch-regulated sexual reproduction in C. tropicalis has important implications for how the species can generate both phenotypic and genetic plasticity. The experiments outlined in this proposal will determine how the novel white-opaque switch in C. tropicalis is regulated, and how phenotypic switching and sexual reproduction influence the organism's interaction with the host. Understanding how the different aspects of C. tropicalis biology affect its virulence will enhance our knowledge of how this species is so well suited to grow in the mammalian host both as a commensal and a pathogen.

描述（由申请人提供）：念珠菌属物种包括作为天然共生体存在的真菌物种，但如果宿主免疫系统受到损害，则可能会致病。尽管白色念珠菌是最常见的真菌病原体，但热带念珠菌引起的感染在世界范围内有所增加。尽管热带念珠菌感染很重要并且死亡率很高，但仍将其确定为一种新兴病原体。 重要的是，我的初步实验发现了热带念珠菌的一种新形式的表型转换，并且基于这些发现，这种转换调节了该物种的有性生殖的神秘程序。 ，该提案将解决热带念珠菌的这些新发现的方面如何影响其发病机制，由于表型可塑性可以通过允许生物体快速适应不断变化的环境来提供适应性优势，因此研究热带念珠菌的表型状态非常重要。热带假丝酵母以及它们如何增强该物种的定殖和感染能力 因此，目标 1 中概述的实验将检查热带念珠菌的白色和不透明表型状态的调节，以及它们在毒力和组织特异性方面的差异。对于本提案的第二个目标，我将讨论交配周期的情况。在热带念珠菌中完成，以及交配如何影响该物种的毒力。实验概述于。 目标 2.1 将阐明热带念珠菌有性周期中倍性减少的机制，因为重组后代产生的遗传变异对生物体的生存和适应应激环境的能力有影响，因此，确定了一种机制。倍性减少和重组对于分析该物种在主要克隆但有性繁殖的种群中产生遗传多样性的能力非常重要，而且，类交配中包含的信息也很重要。基因座（MTL）预计会影响念珠菌属物种的毒力，因为 MTLa/α 白色念珠菌菌株已被证明比其纯合 a/a 或 α/α 菌落的毒力更强。性位点也会改变热带念珠菌分离株的毒力，目标 2.2 将检查 MTLa/a、α/α 和 a/α 分离株在定植时的竞争适应性。这些实验将使我们能够更全面地了解性别决定位点的信息如何有助于热带念珠菌分离株定殖和感染哺乳动物宿主的能力。总体而言，我发现了热带念珠菌中开关调节的有性繁殖。对于该物种如何产生表型和遗传可塑性具有重要意义。本提案中概述的实验将确定如何调节热带念珠菌中的新型白色不透明转换，以及表型转换和有性生殖如何影响。了解热带念珠菌生物学的不同方面如何影响其毒力将增强我们对该物种如何非常适合作为共生体和病原体在哺乳动物宿主中生长的了解。

项目成果

Parasexuality and ploidy change in Candida tropicalis.

热带假丝酵母的副性行为和倍性变化。

• 发表时间: 2013-12
• 作者: Seervai, Riyad N H;Jones Jr, Stephen K;Hirakawa, Matthew P;Porman, Allison M;Bennett, Richard J
• 通讯作者: Bennett, Richard J