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: 7678001
• 负责人: Kirsten Nielsen
• 金额: $ 10.7万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678001
• 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 Genes; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Spinal Puncture; Spleen; Symptoms; Testing; Virulence; Virulence Factors; cancer therapy; cell type; congenic; design; fungus; in vivo; mutant; pathogen; programs; research study; response; trait; treatment strategy

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）：新型隐球菌是一种人类致病真菌，可在免疫功能低下的个体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型隐球菌细胞穿过血脑屏障的能力。虽然过去几年中涉及中枢神经系统（CNS）渗透的过程已被阐明，但新型隐球菌诱导这些过程的方法尚不清楚。有趣的是，C. neoformans 有两种交配类型（a 和 a）；然而，绝大多数临床分离株是交配型。虽然在 a 和 a 菌株同时共感染期间，在最常见致病性隐球菌中同源菌株的个体感染中没有观察到毒力差异，但 a 细胞在中枢神经系统中占主导地位。通过比较个体感染和合并感染中的 a 和 a 细胞，我们有机会识别进入中枢神经系统特别需要的毒力因子。由于新型隐球菌细胞使用信息素感知并响应对方交配伙伴的细胞，因此在初步实验中，我们破坏了a细胞和a细胞的信息素感知，发现信息素信号传导抑制a细胞进入大脑。我们假设信息素信号传导在新型隐球菌进入中枢神经系统中发挥核心作用，并且该信息素信号传导的下游靶标影响新型隐球菌与血脑屏障的相互作用。我们建议通过使用信息素感应或信息素产生改变的突变株扰乱体内信息素信号来测试这些假设。这些突变菌株的毒力将在个体和混合感染中进行检查，并用于通过微阵列分析帮助识别该信息素信号传导的下游靶标。然后，该信息将用于检查影响中枢神经系统进入的细胞特征的变化。此外，将在感染过程中检查信息素水平，以确定何时信息素信号可能对潜在毒力很重要。这些研究将能够识别隐球菌渗透中枢神经系统的关键成分，并为旨在减少中枢神经系统渗透以减轻疾病症状并允许增加抗真菌药物暴露的治疗策略奠定基础。

项目成果

Ste50 adaptor protein governs sexual differentiation of Cryptococcus neoformans via the pheromone-response MAPK signaling pathway.

• DOI: 10.1016/j.fgb.2010.10.006
• 发表时间: 2011-02
• 期刊: FUNGAL GENETICS AND BIOLOGY
• 影响因子: 3
• 作者: Jung, Kwang-Woo;Kim, Seo-Young;Okagaki, Laura H.;Nielsen, Kirsten;Bahn, Yong-Sun
• 通讯作者: Bahn, Yong-Sun

Hrk1 plays both Hog1-dependent and -independent roles in controlling stress response and antifungal drug resistance in Cryptococcus neoformans.

• DOI: 10.1371/journal.pone.0018769
• 发表时间: 2011-04-13
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Kim SY;Ko YJ;Jung KW;Strain A;Nielsen K;Bahn YS
• 通讯作者: Bahn YS

Two cation transporters Ena1 and Nha1 cooperatively modulate ion homeostasis, antifungal drug resistance, and virulence of Cryptococcus neoformans via the HOG pathway.

• DOI: 10.1016/j.fgb.2012.02.001
• 发表时间: 2012-04
• 期刊: FUNGAL GENETICS AND BIOLOGY
• 影响因子: 3
• 作者: Jung, Kwang-Woo;Strain, Anna K.;Nielsen, Kirsten;Jung, Kwang-Hwan;Bahn, Yong-Sun
• 通讯作者: Bahn, Yong-Sun