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; 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）：白色念珠菌在人体的微生物中普遍存在，作为共生和病原体的成功，其成功依赖于适应宿主生理学变化的能力。然而，尽管它作为机会性病原体，但导致表型可塑性和发病机理的机制却很差。该提案将确定有性繁殖在增加表型多样性并促进哺乳动物宿主中多个部位感染的作用。此外，它将探索性信号通路的成分是否代表了抗真菌疗法的新靶标。 白色念珠菌最初被认为是无性的，但现在已经建立了一个有效而精心的交配程序，可以产生生物体的重组形式。白色念珠菌中的交配是独一无二的，因为它受到表型切换的调节。只有不透明的生物体才能进行有性繁殖。此外，尚未观察到减数分裂，而是细胞经历一致的染色体损失程序，以完成偏执式交配周期。寄生态循环的后代是重组菌株，表现出不同的表型，可能会增加宿主的毒力。通过使用体外和体内测定法分析一组后代菌株，将解决这种可能性。寄生态周期的许多产物是载有染色体副本的非整倍体菌株。由于白色念珠菌的抗药性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副后代是否包括耐药性升高的后代。 据认为，白色念珠菌和相关酵母中的有性繁殖仅在A和交配伙伴之间发生。然而，初步实验表明，在有机体中的单性种群中，同性交配存在一种新的机制。自分泌信息素信号传导负责促进自我交配，并且将通过遗传方法建立自分泌信号的机制。这些研究还对相关念珠菌物种的有性繁殖机制具有重要意义，这些机制仅作为单性种群传播。 最后，我们的研究将研究是否可以将性机械的组成部分促进真菌细胞杀死。初步实验表明，性信息素起作用可降低反应细胞的细胞完整性。信号传导的机制将被定义，并测试了可以通过靶向信息素信号途径来增强常见抗真菌药物的细胞杀死的可能性。 公共卫生相关性：白色念珠菌是人类最常见的真菌病原体，既会使粘膜感染和威胁生命的全身感染。我们的研究着重于白色念珠菌新近确定的交配周期的几个方面：（1）对白色念珠菌交配周期的基本生物学的理解及其如何促进哺乳动物宿主中的生存，（2）交配周期的能力与抗毒力或耐药性或抗药性更改的反应性静止性的能力，以及（3）代表犬的潜在表现，该犬能是对犬的潜在表现。