Unraveling Cryptococcus neoformans mechanisms of brain invasion and colonization

揭示新型隐球菌脑侵袭和定植机制

基本信息

批准号：
10409726
负责人：
Luis R Martinez
金额：
$ 45.19万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10409726
关键词：
Acquired Immunodeficiency Syndrome Actins Address Adhesions Antifungal Agents Area Blood - brain barrier anatomy Blood Circulation Brain Cell membrane Cell physiology Cells Central Nervous System Infections Cerebral Cryptococcosis Cerebrospinal Fluid Complex Cryptococcal Meningitis Cryptococcosis Cryptococcus Cryptococcus neoformans Cytoskeleton Data Detection Development Diagnosis Disease Encapsulated Endothelial Cells Endothelium Equus caballus F2R gene Fungal Meningitis Goals Growth HIV-1 Human Immune Incidence Infection Inhalation Intercellular Junctions Interleukin-6 Invaded Laboratories Lymphatic System MAP Kinase Gene Meningoencephalitis Microbe Microglia Molecular Morbidity - disease rate Neuraxis Neurotropism Pathogenesis Pathologic Patients Penetration Permeability Phagocytes Pharmacology Phosphorylation Polysaccharides Predisposition Preventive measure Process Production Proteins Purinoceptor Role Serum Signal Transduction Site Structure of parenchyma of lung TLR2 gene Therapeutic Tight Junctions Yeasts base beta-arrestin blood-brain barrier disruption brain cell brain endothelial cell brain tissue cadherin 5 capsule cell motility cerebral capillary combat cytokine fungus glucuronoxylomannan in vivo insight junctional adhesion molecule migration mimetics mortality mouse model novel novel therapeutics p38 Mitogen Activated Protein Kinase palmidrol polymerization prevent therapeutic target

Acquired Immunodeficiency Syndrome Actins Address Adhesions Antifungal Agents Area Blood - brain barrier anatomy Blood Circulation Brain Cell membrane Cell physiology Cells Central Nervous System Infections Cerebral Cryptococcosis Cerebrospinal Fluid Complex Cryptococcal Meningitis Cryptococcosis Cryptococcus Cryptococcus neoformans Cytoskeleton Data Detection Development Diagnosis Disease Encapsulated Endothelial Cells Endothelium Equus caballus F2R gene Fungal Meningitis Goals Growth HIV-1 Human Immune Incidence Infection Inhalation Intercellular Junctions Interleukin-6 Invaded Laboratories Lymphatic System MAP Kinase Gene Meningoencephalitis Microbe Microglia Molecular Morbidity - disease rate Neuraxis Neurotropism Pathogenesis Pathologic Patients Penetration Permeability Phagocytes Pharmacology Phosphorylation Polysaccharides Predisposition Preventive measure Process Production Proteins Purinoceptor Role Serum Signal Transduction Site Structure of parenchyma of lung TLR2 gene Therapeutic Tight Junctions Yeasts base beta-arrestin blood-brain barrier disruption brain cell brain endothelial cell brain tissue cadherin 5 capsule cell motility cerebral capillary combat cytokine fungus glucuronoxylomannan in vivo insight junctional adhesion molecule migration mimetics mortality mouse model novel novel therapeutics p38 Mitogen Activated Protein Kinase palmidrol polymerization prevent therapeutic target

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项目摘要

Abstract The encapsulated fungus Cryptococcus neoformans (Cn) is the most common cause of fungal meningitis, with the highest rate of cryptococcosis found in AIDS patients. Despite antifungal treatment, cryptococcal meningitis is known for its high morbidity and mortality rates due to its difficult eradication from the brain. Cn’s capsule contributes directly to its pathogenesis; specifically, its main component, glucuronoxylomannan (GXM), has been associated with invasion of the brain. Studies in mouse models of cryptococcal meningoencephalitis have indicated that the portals of Cn invasion into the brain are the cerebral capillaries, which have been confirmed by pathological studies in human brain tissues. Cn can cross the blood brain barrier (BBB) as free yeast either transcellularly using the Trojan horse mechanism, and/or by paracellular passage. However, the fungal factor(s) supporting these invasive processes is/are not well-described. Therefore, the goal of this application is to dissect the cellular and signaling mechanisms by which Cn GXM dysregulates the BBB, allowing the fungus to invade the central nervous system (CNS). Furthermore, microglial (MG) cells are the main form of active immune defense in the CNS. These cells are critical for combating CNS-invading microbes, including Cn, but the specific function(s) of MG cells required to counteract GXM’s BBB damage and Cn invasion is/are poorly understood. Our central hypothesis is that GXM disrupts endothelial cells junctions and inhibits MG cell migration resulting in Cn invasion and colonization of the CNS. To address our hypothesis, we propose the following aims: (1) Determine the role of Cn GXM on BBB physical integrity in vivo; (2) Establish the cell signaling mechanisms by which Cn GXM induces human brain microvascular endothelial cell barrier permeability; and (3) Study the impact of GXM-induced inhibition of MG cell migration and control of Cn brain invasion in vivo. Identification of the mechanisms by which Cn GXM alters the BBB integrity and MG cell functions will provide novel insights into the neurotropism of this deadly infection and may offer new therapeutic opportunities and preventive measures for combating cerebral cryptococcosis, a disease that kills ~200,000 AIDS patients annually around the world.

抽象的封装的真菌新构造（CN）是真菌脑膜炎的最常见原因，在艾滋病患者中发现的隐球菌病的最高率。尽管抗真菌治疗，但隐球菌脑膜炎由于其从大脑中难以消除，以其高发病率和死亡率而闻名。 CN的胶囊直接促进其发病机理；具体而言，其主要成分，糖氧基瘤（GXM）已是与大脑入侵有关。在小鼠脑膜脑炎的小鼠模型中的研究具有表明CN入侵大脑的门户是大脑毛细血管，已被证实通过人脑组织中的病理研究。 CN可以作为游离酵母穿越血脑屏障（BBB）使用特洛伊木马机构和/或细胞细胞传递跨细胞。但是，真菌因子支持这些侵入性过程尚未得到很好的描述。因此，此应用的目的是剖析 CN GXM使BBB失调的细胞和信号传导机制，使真菌入侵中枢神经系统（CNS）。此外，小胶质细胞（MG）细胞是主动免疫的主要形式中枢神经系统的防守。这些细胞对于在包括CN在内的CNS的微生物中对抗至关重要应对GXM的BBB损伤和CN侵袭所需的MG细胞功能尚不清楚。我们的中心假设是GXM破坏了内皮细胞连接并抑制MG细胞迁移在中枢神经系统的CN入侵和定殖中。为了解决我们的假设，我们提出以下目的：（1）确定CN GXM对体内BBB物理完整性的作用；（2）通过 CN GXM影响人脑微血管内皮细胞屏障的渗透性；（3）研究影响 GXM诱导的MG细胞迁移抑制和对体内CN脑侵袭的控制。识别 CN GXM改变BBB完整性和MG细胞功能的机制将为您提供新的见解这种致命感染的神经性神经，并可能提供新的治疗机会和预防措施打击脑隐球菌病，这种疾病每年杀死约200,000名艾滋病患者。