Genetic Regulation of Heritable Switching in Candida albicans

项目摘要 白色念珠菌是一种共生物种，占据着人体不同的生态位。它是 也是一种普遍的机会性病原体，经常引起虚弱的粘膜感染和 危及生命的系统性感染。在许多情况下，共生形态负责播种。 全身性疾病，通常由宿主免疫力崩溃引起。尽管它在临床上 重要的是，对白色念珠菌和白念珠菌之间的共生相互作用的了解仍然有限。 宿主，或在播散性感染期间影响入侵和疾病的真菌特性。 白念珠菌最显著的特征之一是它能够在不同的可遗传状态下生长 和形态形态。在不同表型状态之间转换的能力可以 适应宿主的生态位并调节与免疫系统的相互作用。表观遗传机制 已经被证明可以调节细胞状态之间的可遗传切换，但目前尚不清楚为什么只有一些 临床分离株经历某些表型转换，或细胞状态之间的转换如何决定 与主人互动的结果。 我们现在提出了白念珠菌重要的细胞状态转变的遗传机制。 这既会影响共生行为，也会影响致病行为。白念珠菌是一种杂合二倍体物种。 我们做了意想不到的观察，许多临床分离株即将经历 由于一个关键转录因子在功能上杂合而导致的分化。此外，这样的 杂合子菌株在两种情况下经常丢失转录因子基因的功能拷贝 实验室培养和宿主感染期间。这一变革性事件的直接后果是 在共生和播散性感染模型中产生一种高度竞争的细胞状态。 当前项目的目标是(1)确定主转录因子的变化 基因指示临床上相关的表型开关，(2)定义转录因子基因是否 代表突变和/或重组事件的基因组热点，以及(3)检查细胞 哺乳动物宿主感染过程中的状态转换事件以及不同细胞的特性 在共生和致病感染模式中定义真菌行为的州。 拟议的研究将为白念珠菌如何适应不同的生态位提供新的见解。 寄主，包括一种意想不到的遗传多态和基因组可塑性的机制 结合起来推动细胞分化。这些实验将为C. 白念珠菌生物学，因为很可能其他杂合子基因座类似地为 在宿主中推动适应。

Project Summary Candida albicans is a commensal species that occupies diverse niches of the human body. It is also a prevalent opportunistic pathogen, being a frequent cause of debilitating mucosal infections and life-threatening systemic infections. In many cases, the commensal form is responsible for seeding systemic disease, which is often precipitated by a breakdown in host immunity. Despite its clinical importance, there remains limited understanding of commensal interactions between C. albicans and the host, or the fungal traits that influence invasion and disease during a disseminated infection. One of the most notable attributes of C. albicans is its ability to grow in different heritable states and morphological forms. The ability to transition between different phenotypic states can enable adaptation to host niches and modulate interactions with the immune system. Epigenetic mechanisms have been shown to regulate heritable switching between cell states, yet it is not known why only some clinical isolates undergo certain phenotypic switches, or how transitions between cell states determines outcomes in interactions with the host. We now propose a genetic mechanism underlies an important cell state transition in C. albicans that impacts both commensal and pathogenic behavior. C. albicans is a heterozygous diploid species and we made the unexpected observation that many clinical isolates are poised to undergo differentiation due to being functionally heterozygous for a key transcription factor. Furthermore, such heterozygous strains frequently lose the functional copy of the transcription factor gene both during laboratory culture and during infection of the host. The direct consequence of this transformative event is generation of a cell state that is hypercompetitive both in commensal and disseminated infection models. The goals of the current project are (1) to establish that changes in a master transcription factor gene direct a clinically relevant phenotypic switch, (2) to define whether the transcription factor gene represents a genomic hotspot for mutagenesis and/or recombination events, and (3) to examine cell state transition events during infection of the mammalian host, as well as the properties of different cell states that define fungal behavior in commensal and pathogenic models of infection. The proposed studies will provide new insights into how C. albicans adapts to different niches in the host, including an unexpected mechanism by which genetic polymorphisms and genomic plasticity combine to drive cell differentiation. These experiments will establish an important paradigm for C. albicans biology, as it is likely that other heterozygous loci are similarly primed for genetic events that drive adaptation in the host.