Pheromone Signaling, Sex, and Virulence in Candida albicans

描述(申请人提供)：白色念珠菌普遍存在于人体的微生物区系中，其作为共生菌和病原体的成功依赖于其适应宿主生理变化的能力。然而，尽管它作为一种机会性病原体普遍存在，但其表型可塑性和发病机制尚不清楚。这项建议将确定有性繁殖在增加表型多样性和促进哺乳动物宿主中多个部位的感染方面的作用。此外，它还将探索性信号通路的组成部分是否代表了抗真菌治疗的新靶点。白念珠菌最初被认为是必然无性的，但现在已经建立了一种有效和复杂的交配程序，可以产生重组形式的生物体。白念珠菌的交配是独一无二的，因为它受表型转换的调节；只有不透明的有机体才能进行有性繁殖。此外，没有观察到减数分裂，相反，细胞经历了协调一致的染色体丢失程序，以完成无性交配周期。来自无性繁殖周期的后代是重组菌株，它们表现出不同的表型，有可能增加宿主的毒力。这种可能性将通过使用体外和体内试验对一组后代菌株进行分析来解决。许多无性生殖周期的产物都是携带额外染色体拷贝的非整倍体菌株。由于耐药的白色念珠菌分离株经常表现出染色体拷贝数的变化，我们的研究还将确定是否包括那些抗药性增强的性交后代。白念珠菌和相关酵母菌的有性繁殖被认为只发生在交配伴侣之间。然而，初步实验表明，在生物体的单性种群中存在一种新的同性交配机制。自分泌信息素信号负责促进自交，自分泌信号的机制将通过遗传途径来建立。这些研究还对完全作为单性种群繁殖的相关念珠菌物种的有性繁殖机制具有重要的意义。最后，我们的研究将调查性机制的组成部分是否可以有针对性地促进对真菌细胞的杀灭。初步实验表明，性信息素会降低反应细胞的细胞完整性。将定义信号传递的机制，并测试通过以信息素信号传递通路为靶点来增强普通抗真菌药物对细胞的杀伤的可能性。 公共卫生相关性：白色念珠菌是人类最常见的真菌病原体，可引起衰弱的粘膜感染和危及生命的系统性感染。我们的研究集中在新发现的白色念珠菌交配周期的几个方面：(1)了解白色念珠菌交配周期的基本生物学及其如何促进哺乳动物宿主的生存；(2)交配周期产生毒力或耐药性改变的重组菌株的能力；以及(3)交配回路组件代表抗真菌治疗新靶点的可能性。

DESCRIPTION (provided by applicant): Candida albicans is ubiquitously present in the microflora of the body and its success as both a commensal and a pathogen relies on its ability to adapt to changes in host physiology. However, despite its prevalence as an opportunistic pathogen, the mechanisms contributing to phenotypic plasticity and pathogenesis are poorly defined. This proposal will establish the role of sexual reproduction for increasing phenotypic diversity and promoting infection of multiple sites in the mammalian host. In addition, it will explore if components of the sexual signaling pathway represent novel targets for antifungal therapies. C. albicans was originally thought to be obligately asexual but an efficient and elaborate mating program has now been established that can generate recombinant forms of the organism. Mating in C. albicans is unique in that it is regulated by phenotypic switching; only opaque forms of the organism can undergo sexual reproduction. In addition, meiosis has not been observed and instead cells undergo a program of concerted chromosome loss to complete a parasexual mating cycle. Progeny from the parasexual cycle are recombinant strains that exhibit divergent phenotypes with the potential for increased virulence in the host. This possibility will be addressed by analysis of a set of progeny strains using in vitro and in vivo assays. Many of the products of the parasexual cycle are aneuploid strains carrying extra copies of chromosomes. As drug-resistant isolates of C. albicans often exhibit changes in chromosome copy number our studies will also determine if parasexual progeny include those with increased drug resistance. Sexual reproduction in C. albicans and related yeast is thought to occur exclusively between a and a mating partners. However, preliminary experiments show a novel mechanism exists for same-sex mating within unisexual populations of the organism. Autocrine pheromone signaling is responsible for promoting self-mating and the mechanism of autocrine signaling will be established by genetic approaches. These studies also have important implications for mechanisms of sexual reproduction in related Candida species that propagate exclusively as unisexual populations. Finally, our studies will investigate if components of the sexual machinery can be targeted to promote killing of fungal cells. Preliminary experiments suggest that sexual pheromones act to reduce the cellular integrity of responding cells. The mechanism of signaling will be defined and the possibility tested that cell killing by common antifungal drugs can be potentiated by targeting of pheromone-signaling pathways. PUBLIC HEALTH RELEVANCE: Candida albicans is the most common fungal pathogen in humans, causing both debilitating mucosal infections and life-threatening systemic infections. Our research focuses on several aspects of the newly identified mating cycle in C. albicans: (1) An understanding of the basic biology of the C. albicans mating cycle and how it promotes survival in a mammalian host, (2) The ability of the mating cycle to generate recombinant strains with altered virulence or drug resistance, and (3) The potential for components of the mating circuitry to represent novel targets for antifungal therapies.