Phenotypic Plasticity and Sexual Reproduction in Candida tropicalis Pathogenesis

描述(申请人提供)：假丝酵母菌包括以自然共生形式存在的真菌物种，但如果宿主免疫系统受到损害，可能会变得致病。虽然白色念珠菌是最常见的真菌病原体，但由于热带念珠菌的感染在全球范围内有所增加，使其成为一种新的病原体。尽管热带毛滴虫感染的重要性和与此相关的高死亡率 作为一个物种，人们对它的生命周期以及它如何影响疾病知之甚少。值得注意的是，我的初步实验已经在热带毛虫中发现了一种新的表型转换形式，这种转换调控着这个物种的有性繁殖的神秘程序。基于这些发现，这项建议将解决这些新发现的热带毛滴虫如何影响其发病机制。由于表型可塑性可以使有机体迅速适应不断变化的环境，因此研究热带毛虫的表型状态及其对该物种定居和感染 哺乳动物宿主。因此，目标1中概述的实验将检查热带锥虫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。对于这项提议的第二个目的，我将阐述热带锥虫的交配周期是如何完成的，以及交配如何影响该物种的毒力。中概述的实验 目的2.1将阐明热带梭子蟹有性周期倍性减少的机制，因为重组后代的产生可能导致遗传变异，从而影响生物体生存和适应应激环境的能力。因此，确定倍性减少和重组的机制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将是重要的。此外，交配型基因座(MTL)上包含的信息预计会影响念珠菌的毒力，因为MTLa/？的白色念珠菌菌株已被证明比它们纯合的a/a或？/？菌株的毒力更强。为了确定性基因座上的信息是否也改变了热带毛滴虫分离物的毒力，Aim 2.2将检查MTLa/a、？/？和a/？分离物在寄主定殖中的竞争适合性。这些实验将使人们能够更彻底地了解性别决定基因的信息如何有助于热带毛滴虫分离株定植和感染哺乳动物宿主的能力。总体而言，我对热带梭子蟹开关调控有性繁殖的发现，对于该物种如何产生表型和遗传可塑性具有重要的启示。这项提案中概述的实验将确定热带毛虫中新的白色不透明开关是如何调节的，以及表型转换和有性繁殖如何影响有机体与宿主的相互作用。了解热带毛滴虫生物学的不同方面是如何影响其毒力的，将增强我们对该物种如何如此适合作为共生和病原体在哺乳动物宿主中生长的知识。

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/¿ have been shown to be more virulent than their homozygous a/a or ¿/¿ 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, ¿/¿, and a/¿ 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.