Pheromone Signaling, Sex, and Virulence in Candida albicans

白色念珠菌的信息素信号、性别和毒力

• 批准号: 8303366
• 负责人: Richard John Bennett
• 金额: $ 38.33万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303366
• 关键词: Address; Affect; Aneuploidy; Animal Model; Antifungal Agents; Antifungal Therapy; Autocrine Communication; Biological Assay; Biology; Candida; Candida albicans; Candidiasis; Cell Death; Cell Survival; Cell Wall; Cell membrane; Cells; Cessation of life; Chromosomal Instability; Chromosomes; Diploidy; Disease; Drug resistance; Exhibits; Fungal Drug Resistance; Genetic; Genetic Variation; Human; In Vitro; Infection; Invaded; Laboratories; Life; Mating Types; Meiosis; Microbial Biofilms; Modeling; Molecular; Organism; Partner in relationship; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phenotype; Pheromone; Physiology; Population; Prevalence; Property; Recombinants; Reproduction; Research; Role; Sepsis; Sex Attractants; Signal Pathway; Signal Transduction; Site; Systemic infection; Testing; Variant; Virulence; Work; Yeasts; asexual; autocrine; cell killing; chromosome loss; experience; fungus; gastrointestinal; in vivo; killings; novel; oral infection; pathogen; programs; public health relevance; reproductive; research study; respiratory; response; sex; stressor; success

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.

描述（由申请人提供）：白色念珠菌普遍存在于人体的微生物群中，它作为共生菌和病原体的成功依赖于它适应宿主生理变化的能力。然而，尽管它作为一种机会致病菌普遍存在，但导致表型可塑性和发病机制的机制尚不明确。这一建议将确立有性生殖在增加表型多样性和促进哺乳动物宿主多位点感染方面的作用。此外，它将探索性信号通路的组成部分是否代表抗真菌治疗的新靶点。白色念珠菌最初被认为是绝对无性的，但现在已经建立了一个有效而复杂的交配程序，可以产生重组形式的有机体。白色念珠菌的交配是独特的，因为它是由表型转换调节的；只有不透明的生物体才能有性繁殖。此外，减数分裂没有被观察到，相反，细胞经历一个协调一致的染色体丢失程序来完成一个拟性交配周期。从准性循环的后代是重组菌株，表现出不同的表型，在宿主中具有增加毒力的潜力。这种可能性将通过使用体外和体内试验分析一组后代菌株来解决。许多副性循环的产物是非整倍体菌株，携带额外的染色体拷贝。由于耐药白色念珠菌的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副性后代包括那些耐药增加的后代。白色念珠菌和相关酵母菌的有性繁殖被认为只发生在一对配偶之间。然而，初步实验表明，在单性种群中存在一种新的同性交配机制。自分泌信息素信号是促进植物自交配的重要信号，其作用机制将通过遗传途径来建立。这些研究也对单性繁殖的相关念珠菌物种有性繁殖的机制具有重要意义。最后，我们的研究将调查性机制的组成部分是否可以促进真菌细胞的杀伤。初步实验表明，性信息素的作用是降低应答细胞的细胞完整性。信号传导的机制将被明确，并测试通过靶向信息素信号通路来增强普通抗真菌药物杀死细胞的可能性。