Phenotypic Plasticity and Sexual Reproduction in Candida tropicalis Pathogenesis

描述（由申请方提供）：念珠菌属包括作为天然真菌存在的真菌，但如果宿主免疫系统受损，则可能成为致病菌。虽然白色念珠菌是最常见的真菌病原体，但由于热带念珠菌引起的感染在世界范围内增加，使其成为一种新兴的病原体。尽管C.热带感染和与此相关的高死亡率 然而，对于这一物种的生命周期及其对疾病的影响知之甚少。值得注意的是，我的初步实验已经确定了C.这一开关调节着这一物种有性生殖的神秘程序。基于这些发现，本建议将解决这些新发现的C。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变化的环境来提供适应性优势，因此研究C.以及它们如何有助于这种物种的殖民和感染能力， 哺乳动物宿主因此，目标1中概述的实验将检查C的白色和不透明表型状态的调节。tropicalis，以及它们在毒力和组织特异性方面的差异。对于这个建议的第二个目标，我将在C中说明交配周期是如何完成的。tropicalis，以及交配如何影响该物种的毒性。中概述的实验 目的2.1阐明在有性周期中倍性降低的机制。tropicalis，因为重组后代的产生可能导致的遗传变异对生物体的生存和适应压力环境的能力有影响。因此，确定倍性减少和重组的机制将是重要的分析能力，这个物种产生的遗传多样性，主要是克隆，但有性繁殖，人口。此外，在交配型样基因座（MTL）所包含的信息预计会影响念珠菌属的毒力，如C。MTLa/<$的白色念珠菌菌株已显示比它们的纯合a/a或<$/<$对应物更具毒性。为了确定性位点的信息是否也改变了C.为了确定MTLa/a、MTLa/a和MTLa/a这些实验将使我们能够更深入地了解性别决定基因座上的信息是如何影响C。热带假单胞菌分离株定殖并感染哺乳动物宿主。总的来说，我在C. tropicalis对于该物种如何产生表型和遗传可塑性具有重要意义。在这个建议中概述的实验将确定如何在C中的新的白色不透明开关。热带小蠊的基因调控，以及表型转换和有性繁殖如何影响生物体与宿主的相互作用。理解C语言的不同方面。热带小蠊生物学影响其毒力的研究将增强我们对该物种如何非常适合作为寄生虫和病原体在哺乳动物宿主中生长的认识。

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.