Unraveling Cryptococcus neoformans mechanisms of brain invasion and colonization

揭示新型隐球菌脑侵袭和定植机制

• 批准号: 10624974
• 负责人: Luis R Martinez
• 金额: $ 45.03万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624974
• 关键词: Acquired Immunodeficiency Syndrome; Actins; Address; Adhesions; Antifungal Agents; Area; Blood - brain barrier anatomy; Blood Circulation; Brain; Cell Adhesion Molecules; Cell membrane; Cell physiology; Cells; Central Nervous System; 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; Neurotropism; PIK3CG gene; Pathogenesis; Pathologic; Patients; Penetration; Permeability; Phagocytes; Phosphorylation; Polymers; Polysaccharides; Predisposition; Preventive measure; Process; Production; Proteins; Purinoceptor; Role; Serum; Signal Transduction; Site; Structure of parenchyma of lung; TLR2 gene; Therapeutic; Tight Junctions; Yeasts; beta-arrestin; blood-brain barrier crossing; blood-brain barrier disruption; brain cell; brain endothelial cell; brain tissue; cadherin 5; capsule; cell motility; cerebral capillary; combat; cytokine; fungus; glial activation; glucuronoxylomannan; in vivo; insight; migration; mimetics; mortality; mouse model; neurotransmission; novel; novel therapeutics; p38 Mitogen Activated Protein Kinase; palmidrol; pharmacologic; polymerization; prevent; therapeutic target

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.

摘要 被包裹的真菌新生隐球菌(CN)是真菌性脑膜炎最常见的原因， 在艾滋病患者中发现的隐球菌病的比率最高。尽管接受了抗真菌治疗，但隐球菌性脑膜炎 以其高发病率和高死亡率而闻名，因为它很难从大脑中根除。CN‘s胶囊 直接与其发病机制有关；具体地说，其主要成分葡萄糖醛酸木甘露聚糖(GXM)一直是 与大脑的入侵有关。隐球菌性脑膜脑炎小鼠模型的研究 提示CN侵入大脑的入口是脑毛细血管，已被证实 通过对人脑组织的病理学研究。CN也可以作为游离酵母通过血脑屏障(BBB) 跨细胞使用特洛伊木马机制，和/或通过细胞旁通道。然而，真菌因素(S) 对这些侵入性过程的支持没有/没有得到很好的描述。因此，这个应用程序的目标是剖析 CN GXM失调血脑屏障，允许真菌入侵的细胞和信号机制 中枢神经系统(CNS)。此外，小胶质细胞(MG)是主动免疫的主要形式 在中枢神经系统的防御。这些细胞对于对抗入侵中枢神经系统的微生物至关重要，包括CN，但特定的 MG细胞对抗GXM的血脑屏障损伤和CN侵袭所需的功能(S)尚不清楚。 我们的中心假设是GXM破坏内皮细胞连接并抑制MG细胞的迁移 在CN对CNS的入侵和殖民中。为了解决我们的假设，我们提出了以下目标：(1) 确定CN GXM在体内对BBB生理完整性的作用；(2)通过以下方式建立细胞信号机制 CN GXM对人脑微血管内皮细胞屏障通透性的影响 GXM抑制MG细胞迁移和控制CN脑侵袭的体内研究。身份识别 CN GXM改变血脑屏障完整性和MG细胞功能的机制将为研究 这种致命感染的神经性，并可能提供新的治疗机会和预防措施 与脑隐球菌病作斗争，这种疾病每年在世界各地导致约20万艾滋病患者死亡。

项目成果

Glucuronoxylomannan intranasal challenge prior to Cryptococcus neoformans pulmonary infection enhances cerebral cryptococcosis in rodents.

• DOI: 10.1371/journal.ppat.1010941
• 发表时间: 2023-04
• 期刊: PLoS pathogens
• 影响因子: 6.7

Understanding the Basis of METH Mouth Using a Rodent Model of Methamphetamine Injection, Sugar Consumption, and Streptococcus mutans Infection.

• DOI: 10.1128/mbio.03534-20
• 发表时间: 2021-03-09
• 期刊: mBio
• 影响因子: 6.4
• 作者: Lee HH;Sudhakara P;Desai S;Miranda K;Martinez LR
• 通讯作者: Martinez LR

Alternative Non-Mammalian Animal and Cellular Methods for the Study of Host-Fungal Interactions.

• DOI: 10.3390/jof9090943
• 发表时间: 2023-09-19
• 期刊: Journal of fungi (Basel, Switzerland)
• 作者: Fusco-Almeida AM;de Matos Silva S;Dos Santos KS;de Lima Gualque MW;Vaso CO;Carvalho AR;Medina-Alarcón KP;Pires ACMDS;Belizario JA;de Souza Fernandes L;Moroz A;Martinez LR;Ruiz OH;González Á;Mendes-Giannini MJS
• 通讯作者: Mendes-Giannini MJS

Autoxidation of a C2-Olefinated Dihydroartemisinic Acid Analogue to Form an Aromatic Ring: Application to Serrulatene Biosynthesis.

• DOI: 10.1021/acs.jnatprod.1c01101
• 发表时间: 2022-04-22
• 期刊: JOURNAL OF NATURAL PRODUCTS
• 影响因子: 5.1
• 作者: Varela, Kaitlyn;Al Mahmud, Hafij;Arman, Hadi D.;Martinez, Luis R.;Wakeman, Catherine A.;Yoshimoto, Francis K.
• 通讯作者: Yoshimoto, Francis K.

Methamphetamine Enhances Cryptococcus neoformans Melanization, Antifungal Resistance, and Pathogenesis in a Murine Model of Drug Administration and Systemic Infection.

甲基苯丙胺增强小鼠给药和全身感染模型中的新型隐球菌黑化、抗真菌耐药性和发病机制。

• DOI: 10.1128/iai.00091-22
• 发表时间: 2022
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Erives,VictorH;Munzen,MelissaE;Zamith-Miranda,Daniel;Hernandez,Hazael;Manepalli,Swetha;Nguyen,LongN;Hamed,MohamedF;Nosanchuk,JoshuaD;Martinez,LuisR
• 通讯作者: Martinez,LuisR