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:10624974
- 负责人:
- 金额:$ 45.03万
- 依托单位:
- 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 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeActinsAddressAdhesionsAntifungal AgentsAreaBlood - brain barrier anatomyBlood CirculationBrainCell Adhesion MoleculesCell membraneCell physiologyCellsCentral Nervous SystemCentral Nervous System InfectionsCerebral CryptococcosisCerebrospinal FluidComplexCryptococcal MeningitisCryptococcosisCryptococcusCryptococcus neoformansCytoskeletonDataDetectionDevelopmentDiagnosisDiseaseEncapsulatedEndothelial CellsEndotheliumEquus caballusF2R geneFungal MeningitisGoalsGrowthHIV-1HumanImmuneIncidenceInfectionInhalationIntercellular JunctionsInterleukin-6InvadedLaboratoriesLymphatic SystemMAP Kinase GeneMeningoencephalitisMicrobeMicrogliaMolecularMorbidity - disease rateNeurotropismPIK3CG genePathogenesisPathologicPatientsPenetrationPermeabilityPhagocytesPhosphorylationPolymersPolysaccharidesPredispositionPreventive measureProcessProductionProteinsPurinoceptorRoleSerumSignal TransductionSiteStructure of parenchyma of lungTLR2 geneTherapeuticTight JunctionsYeastsbeta-arrestinblood-brain barrier crossingblood-brain barrier disruptionbrain cellbrain endothelial cellbrain tissuecadherin 5capsulecell motilitycerebral capillarycombatcytokinefungusglial activationglucuronoxylomannanin vivoinsightmigrationmimeticsmortalitymouse modelneurotransmissionnovelnovel therapeuticsp38 Mitogen Activated Protein Kinasepalmidrolpharmacologicpolymerizationpreventtherapeutic target
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
荚膜真菌新型隐球菌 (Cn) 是真菌性脑膜炎的最常见原因,
尽管进行了抗真菌治疗,但隐球菌性脑膜炎在艾滋病患者中的发病率最高。
由于 Cn 囊膜很难根除,因此其发病率和死亡率很高。
具体来说,其主要成分葡萄糖醛酸木甘露聚糖(GXM)已被
与大脑侵袭有关的隐球菌脑膜脑炎小鼠模型的研究。
表明Cn侵入大脑的门户是脑毛细血管,这一点已被证实
通过对人脑组织的病理学研究发现,Cn 也可以作为游离酵母穿过血脑屏障(BBB)。
然而,使用特洛伊木马机制跨细胞和/或通过细胞旁传代。
支持这些侵入性过程没有得到很好的描述,因此,该应用程序的目标是剖析。
Cn GXM 失调 BBB 的细胞和信号传导机制,从而允许真菌入侵
此外,小胶质细胞(MG)是主动免疫的主要形式。
这些细胞对于对抗中枢神经系统入侵的微生物(包括 Cn)至关重要。
MG 细胞抵抗 GXM 的 BBB 损伤和 Cn 入侵所需的功能知之甚少。
我们的中心假设是 GXM 破坏内皮细胞连接并抑制 MG 细胞迁移,从而导致
为了解决我们的假设,我们提出以下目标:(1)
确定Cn GXM对体内BBB物理完整性的作用(2)建立细胞信号传导机制;
(3)研究Cn GXM诱导人脑微血管内皮细胞屏障通透性的影响;
GXM诱导的MG细胞迁移抑制和Cn脑侵袭的体内鉴定。
Cn GXM 改变 BBB 完整性和 MG 细胞功能的机制将为了解
这种致命感染的神经向性,可能为以下疾病提供新的治疗机会和预防措施
对抗脑隐球菌病,这种疾病每年导致全世界约 200,000 名艾滋病患者死亡。
项目成果
期刊论文数量(20)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Phospholipase B Is Critical for Cryptococcus neoformans Survival in the Central Nervous System.
磷脂酶 B 对于新型隐球菌在中枢神经系统中的生存至关重要。
- DOI:
- 发表时间:2023-04-25
- 期刊:
- 影响因子:6.4
- 作者:Hamed, Mohamed F;Araújo, Glauber Ribeiro de Sousa;Munzen, Melissa E;Reguera;Epstein, Carly;Lee, Hiu Ham;Frases, Susana;Martinez, Luis R
- 通讯作者:Martinez, Luis R
Depletion of Alveolar Macrophages Increases Pulmonary Neutrophil Infiltration, Tissue Damage, and Sepsis in a Murine Model of Acinetobacter baumannii Pneumonia.
在鲍曼不动杆菌肺炎小鼠模型中,肺泡巨噬细胞的耗竭会增加肺部中性粒细胞浸润、组织损伤和脓毒症。
- DOI:
- 发表时间:2020
- 期刊:
- 影响因子:3.1
- 作者:Lee, Hiu Ham;Aslanyan, Lilit;Vidyasagar, Arjun;Brennan, Melissa B;Tauber, Maxine S;Carrillo;Dores, Michael R;Rigel, Nathan W;Martinez, Luis R
- 通讯作者:Martinez, Luis R
Nitric Oxide-Releasing Nanoparticles Are Similar to Efinaconazole in Their Capacity to Eradicate Trichophyton rubrum Biofilms.
释放一氧化氮的纳米颗粒在根除红色毛癣菌生物膜的能力方面与艾非康唑相似。
- DOI:
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Costa;Martinez, Luis R;Bila, Níura Madalena;Friedman, Joel M;Friedman, Adam J;Mendes;Nosanchuk, Joshua D
- 通讯作者:Nosanchuk, Joshua D
Editorial: Pathogenesis of Fungal Biofilms in Different Environmental Conditions and Clinical Outcomes.
社论:不同环境条件下真菌生物膜的发病机制和临床结果。
- DOI:
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Pires, Regina Helena;Martinez, Luis R;Mendes;Stoianoff, Maria Aparecida Resende
- 通讯作者:Stoianoff, Maria Aparecida Resende
Coccidioidomycosis: Epidemiology, Fungal Pathogenesis, and Therapeutic Development.
球孢子菌病:流行病学、真菌发病机制和治疗开发。
- DOI:
- 发表时间:2019-09-15
- 期刊:
- 影响因子:5.4
- 作者:Hernandez, Hazael;Erives, Victor H;Martinez, Luis R
- 通讯作者:Martinez, Luis R
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Luis R Martinez其他文献
Factors Contributing to the Success of NIH-Designated Underrepresented Minorities in Academic and Nonacademic Research Positions
有助于 NIH 指定的代表性不足的少数群体在学术和非学术研究职位上取得成功的因素
- DOI:
- 发表时间:
2018 - 期刊:
- 影响因子:0
- 作者:
Luis R Martinez;Dwayne W. Boucaud;A. Casadevall;A. August - 通讯作者:
A. August
Polymicrobial interactions involving fungi and their importance for the environment and in human disease.
涉及真菌的多微生物相互作用及其对环境和人类疾病的重要性。
- DOI:
10.1016/j.micpath.2019.103942 - 发表时间:
2019-12-24 - 期刊:
- 影响因子:3.8
- 作者:
Seham Z Azzam;Ginelle J Cayme;Luis R Martinez - 通讯作者:
Luis R Martinez
Luis R Martinez的其他文献
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{{ truncateString('Luis R Martinez', 18)}}的其他基金
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:
10409726 - 财政年份:2019
- 资助金额:
$ 45.03万 - 项目类别:
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:
10215538 - 财政年份:2019
- 资助金额:
$ 45.03万 - 项目类别:
Impact of Maternal Methamphetamine Abuse on Neonatal Immunity
母亲滥用甲基苯丙胺对新生儿免疫力的影响
- 批准号:
8336807 - 财政年份:2011
- 资助金额:
$ 45.03万 - 项目类别:
Impact of Maternal Methamphetamine Abuse on Neonatal Immunity
母亲滥用甲基苯丙胺对新生儿免疫力的影响
- 批准号:
8045879 - 财政年份:2011
- 资助金额:
$ 45.03万 - 项目类别:
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