A link between mating pheromone sensing and virulence of Cryptococcus neoformans

交配信息素感应与新生隐球菌毒力之间的联系

• 批准号: 7425136
• 负责人: Kirsten Nielsen
• 金额: $ 16.02万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7425136
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Antifungal Agents; Beds; Blood - brain barrier anatomy; Blood Circulation; Brain; Cells; Central Nervous System Infections; Cerebrospinal Fluid; Characteristics; Clinical; Communicable Diseases; Congenic Strain; Cryptococcal Meningitis; Cryptococcus; Cryptococcus neoformans; Cryptococcus neoformans infection; Diagnosis; Disease; Endothelial Cells; Exposure to; Foundations; Gene Expression; Human; Immunocompromised Host; In Vitro; Individual; Infection; Life; Link; Lung; Mating Types; Meningoencephalitis; Methods; Microarray Analysis; Monitor; Mononuclear; Neuraxis; Partner in relationship; Penetration; Phagocytes; Pheromone; Play; Population; Process; Production; Proliferating; Reporter; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Spinal Puncture; Spinal Tap; Spleen; Symptoms; Testing; Virulence; Virulence Factors; cancer therapy; cell type; congenic; design; fungus; in vivo; mutant; pathogen; programs; research study; response; trait

DESCRIPTION (provided by applicant): Cryptococcus neoformans is a human pathogenic fungus that causes life-threatening meningoencephalitis in immunocompromised individuals. One important aspect of cryptococcosis is the ability of C. neoformans cells to cross the blood-brain barrier. While the processes involved in central nervous system (CNS) penetration have been elucidated over the past few years, the methods by which C. neoformans induces these processes are unknown. Interestingly, C. neoformans has two mating types (a and a); however the vast majority of clinical isolates are a mating type. While no differences in virulence are observed in individual infections with congenic strains in the most commonly pathogenic variety of Cryptococcus during coinfection of a and a strains simultaneously, the a cells predominate in the CNS. By comparing the a and a cells in individual and coinfections we have the opportunity to identify virulence factors specifically required for entry into the CNS. Because C. neoformans cells sense and respond to cells of the opposite mating partner using pheromones, in preliminary experiments we disrupted pheromone sensing in both a and a cells and discovered that a cells are inhibited from entering the brain by pheromone signaling. We hypothesize that pheromone signaling plays a central role in C. neoformans entry into the CNS and that the downstream targets of this pheromone signaling affect the interaction of C. neoformans with the blood-brain barrier. We propose to test these hypotheses by perturbing in vivo pheromone signaling using mutant strains altered in either pheromone sensing or pheromone production. The virulence of these mutant strains will be examined in individual and coinfections and used to help identify the downstream targets of this pheromone signaling by microarray analysis. This information will then be used to examine changes in cellular traits that affect CNS entry. Furthermore, pheromone levels will be examined during the infectious process to define when pheromone signaling is likely to be important for virulence potential. These studies will allow the identification of key components of CNS penetration by Cryptococcus and provide a foundation for treatment strategies designed to reduce CNS penetration to alleviate disease symptoms and allow for increased exposure to antifungal drugs.

描述(由申请人提供)：新生隐球菌是一种人类致病真菌，可在免疫功能受损的人中引起危及生命的脑膜脑炎。隐球菌病的一个重要方面是新生隐球菌细胞穿越血脑屏障的能力。虽然在过去的几年里，涉及中枢神经系统(CNS)穿透的过程已经被阐明，但新生葡萄球菌诱导这些过程的方法尚不清楚。有趣的是，新生葡萄球菌有两种交配型(a和a)；然而，绝大多数临床分离株是交配型。虽然在同时感染a和a株的过程中，最常见的致病变种隐球菌的同源菌株在个体感染中的毒力没有差异，但a细胞在中枢神经系统中占主导地位。通过比较单个感染和联合感染中的a和a细胞，我们有机会确定进入中枢神经系统所需的毒力因子。由于新生隐孢子虫的细胞使用信息素感知并对相反交配伙伴的细胞做出反应，在初步实验中，我们扰乱了a和a细胞的信息素感知，并发现信息素信号阻止了a细胞进入大脑。我们假设信息素信号在新生葡萄球菌进入中枢神经系统中起核心作用，信息素信号的下游靶点影响新生葡萄球菌与血脑屏障的相互作用。我们建议通过扰乱体内信息素信号来验证这些假设，使用在信息素感知或信息素产生方面发生变化的突变菌株。这些突变菌株的毒力将在单独和联合感染中进行检测，并通过微阵列分析帮助确定这种信息素信号的下游靶标。这些信息随后将被用来检查影响中枢神经系统进入的细胞特征的变化。此外，将在感染过程中检测信息素水平，以确定信息素信号可能对毒力潜力起重要作用的时间。这些研究将能够确定隐球菌穿透中枢神经系统的关键成分，并为旨在减少中枢神经系统穿透以缓解疾病症状并允许更多地接触抗真菌药物的治疗策略提供基础。