Cryptococcal Exploitation of the Blood-Brain Barrier

隐球菌对血脑屏障的利用

• 批准号: 10012330
• 负责人: Kwang S Kim
• 金额: $ 24.56万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-17 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012330
• 关键词: Acute; Africa South of the Sahara; Animal Model; Area; Blood - brain barrier anatomy; Brain; CRISPR screen; Cell surface; Central Nervous System Infections; Cessation of life; Consensus Sequence; Cryptococcus; Cryptococcus neoformans; Data; Development; Epidermal Growth Factor Receptor; Exhibits; Experimental Animal Model; Experimental Models; Genes; Goals; HIV; HIV-1; Hematogenous; Human; In Vitro; Inhalation; Integration Host Factors; Knock-out; Knowledge; Lead; Life; Ligand Binding; Ligand Binding Domain; Ligands; Listeria monocytogenes; Membrane; Meningitis; Meningoencephalitis; Modeling; Morbidity - disease rate; Neuraxis; Organ; Pathogenesis; Patients; Penetration; Phosphotransferases; Protein Tyrosine Kinase; Proteins; Public Health; Receptor Activation; Receptor Cell; Receptor Protein-Tyrosine Kinases; Reporting; Role; Site; Structure of choroid plexus; Transmembrane Domain; Tuberculosis; base; blood-brain barrier penetration; brain endothelial cell; cerebral capillary; cerebral microvasculature; complement 1q receptor; extracellular; genome-wide; in vivo; innovation; interest; knock-down; monolayer; mortality; mouse model; novel; receptor; response; small hairpin RNA; transcytosis

Abstract Cryptococcus neoformans (C. neoformans) is an important cause of life-threatening opportunistic central nervous system (CNS) infection in HIV-1-infected patients. For areas of the world where HIV-1 is endemic, C. neoformans is the most common cause of culture-positive meningitis. Several lines of evidence from human cases and experimental animal models of C. neoformans CNS infection indicate that cerebral capillaries are the portal of C. neoformans entry into the brain. Since the entry of C. neoformans into the brain occurred in the cerebral microvasculature, we used the in vitro blood-brain barrier model with human brain microvascular endothelial cells (HBMEC) to investigate cryptococcal penetration of the blood-brain barrier. We showed that C. neoformans exhibited the ability to traverse the HBMEC monolayer in vitro and penetrate into the brain in vivo in the mouse model of experimental hematogenous C. neoformans CNS infection. The underlying mechanisms involved with C. neoformans penetration of the blood-brain barrier, however, remain incompletely understood. Our preliminary screen of HBMEC infected with C. neoformans for determination of host factors revealed globular C1q receptor (gC1qR). The role of gC1qR in C. neoformans penetration of the blood-brain barrier has not been previously recognized, and it remains unclear how gC1qR contributes to cryptococcus penetration of the blood-brain barrier. gC1qR is a multifunctional protein and shown to be expressed on the cell surface. We hypothesize that C. neoformans exploits gC1qR for penetration of the blood-brain barrier, the essential step in the development of cryptococcal CNS infection. This hypothesis is supported by our demonstration that HBMEC with gC1qR knockdown exhibited significantly less C. neoformans penetration. gC1qR does not have a consensus sequence of transmembrane domain, and the goal of this application is to elucidate how gC1qR contributes to C. neoformans penetration of the blood-brain barrier. The innovative aspect of this R21 exploratory application is to investigate a new target (gC1qR) exploited by C. neoformans for penetration of the blood-brain barrier. The information derived from this application will provide a new paradigm for investigating the pathogenesis of C. neoformans CNS infection.

摘要 新型隐球菌（C.新生儿）是危及生命的机会性中枢神经系统疾病的重要原因。 神经系统（CNS）感染的HIV-1感染患者。对于世界上HIV-1流行的地区，C. 新生儿是培养阳性脑膜炎的最常见原因。几条来自人类的证据 病例和实验动物模型。新生儿CNS感染表明脑毛细血管 C的入口。新生儿进入大脑自从C.进入大脑的新形式发生在 脑微血管，我们使用体外血脑屏障模型与人脑微血管， 内皮细胞（HBMEC）研究隐球菌对血脑屏障的渗透。我们发现 C.新生儿在体外表现出穿过HBMEC单层的能力， 在小鼠实验性血源性C.新生儿CNS感染。底层 与C.然而，新生儿对血脑屏障的穿透仍然不完全， 明白我们对感染C.测定宿主因子的新型细菌 结果显示，GC 1 qR为球状C1 q受体。gC 1 qR在C.新生儿对血脑的渗透 屏障以前没有被认识到，目前还不清楚gC 1 qR如何有助于隐球菌 穿透血脑屏障。gC 1 qR是一种多功能蛋白，并显示在细胞上表达 面我们假设C.新生儿利用gC 1 qR穿透血脑屏障， 隐球菌中枢神经系统感染的发展过程中的重要步骤。这一假设得到了我们的支持。 证明gC 1 qR敲低的HBMEC表现出显著更少的C.新型生物的渗透 gC 1 qR不具有跨膜结构域的共有序列，本申请的目的是 阐明gC 1 qR对C.新生儿对血脑屏障的渗透创新 这个R21探索性应用的一个方面是研究C.新生 用于穿透血脑屏障。从这个应用程序中获得的信息将提供一个新的 研究C.新生儿CNS感染。