Parasexual Genetics and Host Adaptation in Candida Fungal Pathogens

描述（由申请人提供）：白色念珠菌是人类微生物组的常规组成部分，在大约70%的健康个体中定植。在这种共生状态下，白色念珠菌在身体的许多粘膜表面定植，包括口腔、呼吸道和胃肠道，而不表现出任何疾病症状。然而，当正常的宿主免疫力受损，或者如果局部微生物群发生变化，白色念珠菌可以迅速成为一种侵袭性的，危及生命的机会性病原体bbb。因此，了解这种灵活病原体的生活方式对保护人类生命至关重要。在过去一个世纪的大部分时间里，白色念珠菌被认为是无性的。这是令人惊讶的，因为许多相关的子囊菌真菌是兼性的。在过去的二十年里，白色念珠菌的一个神秘的交配周期已经被发现。它始于基因组交配型样位点（MTL）[4]的发现，随后发现白色念珠菌在体外和体内都可以很少交配[5,6]。进一步的研究发现，一种被称为“白色不透明开关”的表型开关可以进一步调节交配。为了完成交配程序，白色念珠菌不使用减数分裂，而是使用包括一系列减数分裂的拟性机制，导致多种后代表现出遗传重组和非整倍体[8,9]。为什么这种独特的，严格控制的性程序会进化，以及它对疾病的影响是未知的，这是本研究的中心焦点。本研究将首先解决白色念珠菌副性循环产生的表型和基因组多样性的程度。在实验室的初步研究已经确定，副性途径能够产生表型多样化的后代。然而，表型变异的程度，以及促进适应环境胁迫的能力尚不清楚。因此，本研究将重点研究白色念珠菌的副性循环及其产生抵抗环境压力的后代的能力。此外，本研究旨在确定通过拟交配产生的非整倍性在塑造表型输出中的作用。白色念珠菌利用的性程序包含不同的形态转变，包括白色不透明开关，丝状生长和生物膜形成。本提案第二部分提出的实验旨在确定性程序本身如何直接影响白色念珠菌与哺乳动物宿主相互作用并引起疾病的能力。总的来说，在这个目标中提出的实验有助于建立最近确定的白色念珠菌交配周期，并确定其在产生适应性后代以及直接指导疾病方面的作用。

DESCRIPTION (provided by applicant): Candida albicans is a regular component of the human microbiome, colonizing approximately 70% of healthy individuals [1]. In this commensal state, C. albicans colonizes many mucosal surfaces in the body, including the mouth, respiratory tract, and gastrointestinal tract without presenting any symptoms of disease. However, when regular host immunity is impaired, or if changes in local microflora arise, C. albicans can rapidly become an invasive, life-threatening opportunistic pathogen [2]. It is therefore crucial to understand the life-style of this flexible pathogen to protect human life. Fo most of the past century, C. albicans was believed to be asexual. This was surprising because many related ascomycete fungi are facultatively sexual. During the last two decades, a cryptic mating cycle in C. albicans has become uncovered. It began with the discovery of a genomic mating type-like locus (MTL) [4], which subsequently led to the discovery that C. albicans can mate infrequently in vitro and in vivo [5,6]. Additional work led to the discovery that a phenotypi switch, termed the 'white-opaque switch', regulates mating further [7]. To complete the mating program, C. albicans does not use meiosis, and alternatively utilizes a parasexual mechanism that includes a series of reductional mitotic divisions, resulting in diverse progeny exhibiting genetic recombination and aneuploidy [8, 9]. Why this unique, tightly regulated sexual program has evolved and its impact on disease is unknown, and is the central focus of this study. The research in this study will first address the extent of phenotypic and genomic diversity generated through the C. albicans parasexual cycle. Preliminary studies in the lab have identified that the parasexual pathway is capable of generating phenotypically diverse progeny. However, the extent of phenotypic variation, and the ability to promote adaptation to environmental stress is not clear. Research in this study will therefore focus on investigating the C. albicans parasexual cycle and its ability to produce progeny that are resistant to environmental stress. Additionally, research in this study aims to identify the role that aneuploidy arising through parasex plays in shaping phenotypic output. The sexual program utilized by C. albicans incorporates distinct morphological transitions, including the white-opaque switch, filamentous growth and biofilm formation. The experiments posed in the second portion of this proposal aims to identify how the sexual program itself directly affects the ability of C. albicans to interact with the mammalian host and cause disease. Overall, the experiments proposed in this aim serve to build on the recently identified C. albicans mating cycle, and to identify its role in both generating adaptive progeny, as well directly directing disease.