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[1]。在这种情况下，C.白色念珠菌在身体中的许多粘膜表面（包括口腔、呼吸道和胃肠道）定植而不呈现任何疾病症状。然而，当正常的宿主免疫力受损时，或者如果局部微生物区系发生变化，C。白色念珠菌可迅速成为侵入性的、威胁生命的机会性病原体[2]。因此，了解这种灵活的病原体的生活方式以保护人类生命至关重要。 在过去世纪的大部分时间里，C.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20年里，C.白色念珠菌已被发现。它开始于基因组交配型样位点（MTL）的发现[4]，随后导致C.白色念珠菌在体外和体内很少交配[5，6]。额外的工作导致发现表型开关，称为“白色不透明开关”，进一步调节交配[7]。为了完成交配程序，C。白色念珠菌不使用减数分裂，或者利用包括一系列减数有丝分裂的准性机制，导致表现出遗传重组和非整倍性的不同后代[8，9]。为什么这种独特的，严格管制的性程序已经演变及其对疾病的影响是未知的，这是本研究的中心焦点。 本研究将首先解决通过C.白念珠菌准性周期实验室的初步研究已经确定，准性途径能够产生表型多样的后代。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C。白念珠菌的准性周期及其产生对环境胁迫具有抗性的后代的能力。此外，本研究的研究旨在确定通过parasex产生的非整倍体在形成表型输出中的作用。 C.白色念珠菌具有不同的形态转变，包括白色-不透明转换、丝状生长和生物膜形成。在这个提议的第二部分中提出的实验旨在确定性程序本身如何直接影响C的能力。白色念珠菌与哺乳动物宿主相互作用并引起疾病。总的来说，在这个目标中提出的实验是建立在最近确定的C。白念珠菌交配周期，并确定其在产生适应性后代以及直接指导疾病中的作用。

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.