HOST FACTORS IN CRYPTOCOCCAL PATHOGENESIS

隐球菌发病机制中的宿主因素

基本信息

批准号：
8848028
负责人：
Tamara L Doering
金额：
$ 44.28万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8848028
关键词：
AIDS-Related Opportunistic Infections Acquired Immunodeficiency Syndrome Address Adherence Affect Anabolism Antifungal Therapy Area Biochemical Biochemistry Biological Assay Biology Brain Calcium Calmodulin Cell Line Cell Surface Proteins Cell surface Cells Cessation of life Cryptococcus Cryptococcus neoformans Cryptococcus neoformans infection Data Disease Elements Enzymes Equilibrium Event Funding Gene Expression Glucosamine Goals Health Histology Human Image Immune response Immunity Immunocompromised Host Individual Infection Integration Host Factors Investigation Knockout Mice Libraries Life Lipids Mediating Meningitis Meningoencephalitis Metabolic Methods Microbe Mining Modification Molecular Mus Organ Organism Outcome Pathogenesis Pathway interactions Patients Phagocytes Phagocytosis Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Play Population Post-Translational Protein Processing Process Protein Glycosylation Proteins Proteomics Psyche structure Public Health RNA Reproduction spores Research Resolution Role Severity of illness Sialic Acids Signal Transduction Signaling Protein Small Interfering RNA Suggestion System Testing Virulence Work Yeasts base epimerase fascinate fungus genetic manipulation high throughput screening improved inhibitor/antagonist innovation insight macrophage mouse model pathogen protein expression research study response screening uptake

项目摘要

DESCRIPTION (provided by applicant): Host factors in cryptococcal pathogenesis PROJECT SUMMARY Cryptococcus neoformans is an opportunistic pathogen responsible for life-threatening disease in patients with AIDS or otherwise compromised immunity; extrapulmonary cryptococcal infection is an AIDS-defining illness. Cryptococcosis has a tremendous impact on human health, causing over one million cases of meningitis and 625,000 deaths annually worldwide, with the vast majority of deaths occurring in individuals with AIDS. The long-term goal of our studies is to define host:fungal interactions in C. neoformans pathogenesis, in order to improve both fundamental understanding of these important events and the outcome of this devastating AIDS- related opportunistic infection. This application focuses on the interactions between C. neoformans and host phagocytes, which have been implicated in fungal latency, dissemination, and virulence. Although fungal en- gulfment has been broadly described, little is known about the host factors required to mediate this process, a lack of understanding that impairs our ability to influence this interaction in favor of the host. We recently com- pleted an siRNA screen in a human macrophage-like cell line to identify kinases and phosphatases that act in C. neoformans internalization. We have now shown that two kinases, one involved in cell signaling and one in cell surface modification, are required for efficient fungal internalization b host primary cells. Mice lacking the signaling protein also show reduced dissemination of cryptococcal infection to the brain. We propose to deter- mine the mechanisms of action by which each of these proteins influences phagocytosis, and their effects on the pathogenesis of cryptococcal disease. We will use mouse models and primary cells in focused studies that exploit our expertise in biochemistry, gene expression, host biology, and post-translational modifications to de- termine mechanism. This powerful combination of approaches will elucidate crucial events of pathogenesis that determine survival and dissemination of an opportunistic microbe, and thereby the host's ability to limit disease. Our findings will also illuminate other host:microbe interactions and may suggest new directions for antifungal therapy.

描述（由申请人提供）：隐球菌发病机制中的宿主因素项目摘要新型隐球菌是一种机会性病原体，可导致艾滋病患者或其他免疫力受损的患者罹患危及生命的疾病；肺外隐球菌感染是一种艾滋病定义的疾病。隐球菌病对人类健康具有巨大影响，每年在全球引起超过 100 万例脑膜炎病例和 625,000 人死亡，其中绝大多数死亡发生在艾滋病患者身上。我们研究的长期目标是确定新型隐球菌发病机制中宿主与真菌之间的相互作用，以提高对这些重要事件的基本了解以及这种毁灭性的艾滋病相关机会性感染的结果。该应用重点关注新型隐球菌和宿主吞噬细胞之间的相互作用，这种相互作用与真菌潜伏期、传播和毒力有关。尽管真菌吞噬已被广泛描述，但我们对介导这一过程所需的宿主因素知之甚少，缺乏了解会削弱我们影响这种有利于宿主的相互作用的能力。我们最近在人类巨噬细胞样细胞系中完成了 siRNA 筛选，以鉴定在新型隐球菌内化中起作用的激酶和磷酸酶。我们现在已经证明，宿主原代细胞的有效真菌内化需要两种激酶，一种参与细胞信号传导，另一种参与细胞表面修饰。缺乏信号蛋白的小鼠也显示出隐球菌感染向大脑的传播减少。我们建议确定这些蛋白质影响吞噬作用的作用机制，以及它们对隐球菌疾病发病机制的影响。我们将在重点研究中使用小鼠模型和原代细胞，利用我们在生物化学、基因表达、宿主生物学和翻译后修饰方面的专业知识来确定机制。这种强有力的方法组合将阐明发病机制的关键事件，这些事件决定机会微生物的生存和传播，从而决定宿主限制疾病的能力。我们的研究结果还将阐明其他宿主：微生物的相互作用，并可能为抗真菌治疗提出新的方向。