Role of Calcineurin in Fungal Virulence

钙调神经磷酸酶在真菌毒力中的作用

基本信息

批准号：
7879190
负责人：
JOSEPH HEITMAN
金额：
$ 0.56万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-14 至 2009-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7879190
关键词：
Alleles Animal Model Antifungal Agents Attenuated Award Binding Binding Proteins Binding Sites Biogenesis C2 Domain CALM1 gene Calcineurin Calcineurin B Calcineurin Pathway Calcineurin inhibitor Calcium Calmodulin Candida albicans Catalytic Domain Cell Wall Cells Cryptococcus neoformans Cyclosporine Diploidy Drug Combinations Drug resistance Elements Epitopes FK506 Fungal Meningitis Genes Genetic Screening Growth Haploidy Homeostasis Homologous Gene Human Immunosuppressive Agents Incidence Insertion Mutation Link Mass Spectrum Analysis Mediating Meiosis Microarray Analysis Molecular Molecular Target Mutate Mycoses Partner in relationship Pathway interactions Phosphoproteins Phosphorylation Proliferating Protein Family Protein phosphatase Proteins Research Personnel Role Saccharomycetales Serum Signal Pathway Signal Transduction Stress Temperature Testing Therapeutic Intervention Virulence base fungus inhibitor/antagonist member mutant novel overexpression pathogen prevent programs protein function resistant strain temperature sensitive mutant transcription factor yeast protein yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): The incidence of fungal infection is increasing and yet available antifungal drugs are limited, some are toxic, and drug resistant strains are emerging. We have elucidated a conserved signal transduction cascade that controls virulence of Cryptococcus neoformans, the leading cause of fungal meningitis. The central element of this virulence pathway is the calcium-calmodulin activated protein phosphatase calcineurin, which is the molecular target of the immunosuppressive antifungal drugs cyclosporin A and FK506. C. neoformans mutants lacking either the catalytic A or the regulatory B subunit of calcineurin are inviable at 37 degrees C and other stress conditions and, as a consequence, are avirulent in animal models. In studies supported by this award, we identified: 1) the calcineurin B regulatory subunit and calmodulin, 2) the calcineurin binding protein (Cbpl) that is a conserved regulator or effector and which is the founding member of a protein family conserved from fungi to humans, and 3) the novel C2 domain protein Cts1 that may function as a downstream effector of the calcineurin signaling pathway to promote cell wall biogenesis and growth at 37degrees C. In parallel we discovered that calcineurin is required for virulence of Candida albicans, the most common human fungal pathogen. C. albicans cnb1/cnb1 mutants lacking the calcineurin B regulatory subunit are severely attenuated in animal models. Yet, in contrast to C. neoformans calcineurin is not required for growth of C. albicans at 37 degrees C. Instead, calcineurin is necessary for C. albicans to survive and proliferate in serum. These studies illustrate how a conserved signaling cascade has been co-opted to control virulence of two divergent fungal pathogens by unique molecular mechanisms. Here we propose to delineate this molecular virulence cascade in both C. neoformans and C. albicans. Importantly, this pathway can be targeted for therapeutic intervention using non-immunosuppressive calcineurin inhibitors that retain antifungal activity and synergistic drug combinations that we have discovered.

描述（由申请人提供）：真菌感染的发生率正在增加，但可用的抗真菌药物有限，有些有毒，并且耐药菌株正在出现。我们已经阐明了一个保守的信号转导级联，该级联控制着加密型新甲壳虫的毒力，这是真菌脑膜炎的主要原因。该毒力途径的核心元素是钙 - 钙统蛋白活化的蛋白磷酸酶钙调蛋白，它是免疫抑制抗真菌药物环孢菌素A和FK506的分子靶标。 C. Neoformans突变体缺乏催化A或钙调蛋白的调节B亚基在37摄氏度和其他应力条件下不可或缺，因此在动物模型中是无毒的。 In studies supported by this award, we identified: 1) the calcineurin B regulatory subunit and calmodulin, 2) the calcineurin binding protein (Cbpl) that is a conserved regulator or effector and which is the founding member of a protein family conserved from fungi to humans, and 3) the novel C2 domain protein Cts1 that may function as a downstream effector of the calcineurin signaling pathway to promote细胞壁生物发生和37度C的生长。在平行的情况下，我们发现钙调神经蛋白是白色念珠菌（最常见的人类真菌病原体）毒力所必需的。白色念珠菌CNB1/CNB1突变体缺乏钙调蛋白B调节亚基在动物模型中严重减弱。然而，与新近钙调霉菌蛋白酶的相反，在37摄氏度下白色念珠菌的生长并不是必需的。相反，白色念珠菌在血清中生存和增殖是必要的。这些研究说明了如何通过独特的分子机制来控制保守的信号级联反应以控制两种不同的真菌病原体。在这里，我们提议描绘新梭菌和白色念珠菌中的这种分子毒力级联。重要的是，该途径可以用于使用我们发现的非免疫抑制钙调神经磷酸蛋白抑制剂来进行治疗干预，以保留我们发现的抗真菌活性和协同药物组合。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ras1 and Ras2 contribute shared and unique roles in physiology and virulence of Cryptococcus neoformans.

DOI：
10.1099/00221287-148-1-191
发表时间：
2002
期刊：
Microbiology
影响因子：
1.5
作者：
Michael S. Waugh;Michael S. Waugh;Connie B Nichols;Connie B Nichols;Cameron M DeCesare;G. Cox;J. Heitman;J. Alspaugh
通讯作者：
Michael S. Waugh;Michael S. Waugh;Connie B Nichols;Connie B Nichols;Cameron M DeCesare;G. Cox;J. Heitman;J. Alspaugh

A STE12 homolog is required for mating but dispensable for filamentation in candida lusitaniae.

在卢西塔尼亚假丝酵母中，交配需要 STE12 同系物，但丝状形成则不需要。