Filtering of disseminating Cryptococcus neoformans out of vasculature

将传播的新型隐球菌从脉管系统中过滤出来

• 批准号: 9387721
• 负责人: Meiqing Shi
• 金额: $ 19万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-19 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9387721
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Animals; Blood; Blood Circulation; Blood-Borne Pathogens; Brain; Breathing; Cancer Patient; Cells; Cessation of life; Complement; Complement Receptor; Complication; Cryptococcus neoformans; Cryptococcus neoformans infection; Data; Detection; Development; Discontinuous Capillary; Drops; Encapsulated; Event; Excision; Fungemia; Future; Hepatocyte; Human; Immune; Immune response; Immunocompromised Host; Individual; Infection; Kinetics; Knowledge; Kupffer Cells; Liver; Lung; Macrophage-1 Antigen; Mediating; Meningoencephalitis; Mus; Opportunistic Infections; Organ; Organ Transplantation; Organism; Pathogenicity; Patients; Play; Population; Recruitment Activity; Risk; Role; Spleen; Testing; Therapeutic; Therapeutic immunosuppression; Time; Tissues; Transplant Recipients; Venous; base; fungus; in vivo; insight; intravital microscopy; macrophage; mouse model; novel strategies; novel therapeutic intervention; particle; pathogen; receptor; shear stress

Project Summary Cryptococcosis is an opportunistic infection that occurs in immunocompromised individuals including AIDS patients, organ transplant recipients, cancer patients, and those treated with immunosuppressive therapies. It is estimated there are one million cases of cryptococcosis and proximately 600,000 deaths worldwide annually. The infection starts in the lung via inhalation of the encapsulated fungus Cryptococcus neoformans. However, the major and most lethal complication of cryptococcosis is meningoencephalitis. To cause meningoencephalitis, C. neoformans must disseminate from the lung and enter the bloodstream. As such, fungemia, detected frequently in AIDS patients during cryptococcosis, is believed to be one of the most critical steps in the development and persistence of cryptococcal meningoencephalitis. However, little is known about intravascular clearance of the disseminating C. neoformans due to technical challenge for in vivo studies. In particular, a critical gap in our understanding remains: Does a mechanism exist to actively eliminate disseminating C. neoformans out of vasculature, and what is the mechanism? Liver is situated at a confluence of arterial and venous blood. Kupffer cells (KCs) constitute ~90% of the tissue macrophages in the whole body and account for ~15% of the total liver cell population. CRIg, a unique complement receptor, has been recently identified on KCs of humans and animals. Although the liver is not a target organ of cryptococcosis, we hypothesize, based on our preliminary data, that KCs play a critical role in filtering of disseminating C. neoformans out of circulation via a mechanism involving complement receptor CRIg. We will test the hypothesis by addressing the following aims using intravital microscopy and other advanced approaches: (1) To characterize the role of KCs in filtering C. neoformans out of vasculature; (2) To dissect the mechanism(s) involved in capture of disseminating C. neoformans by KCs. The findings from this study will suggest that a therapeutic strategy aimed at enhancing macrophage recruitment and activity in the liver could help reducing the risk of cryptococcal meningocephalitis in AIDS patients.

项目摘要 隐球菌病是一种机会性感染，发生在免疫功能低下的个人 包括艾滋病患者、器官移植接受者、癌症患者以及接受过 免疫抑制疗法。据估计，有一百万例隐球菌病， 全世界每年约有60万人死亡。感染开始于肺部，通过吸入 包囊真菌新型隐球菌。然而，主要的和最致命的并发症， 隐球菌病是脑膜脑炎C.新人类必须传播 从肺部进入血液因此，在艾滋病患者中经常检测到的真菌血症， 隐球菌病被认为是隐球菌病发展和持续的最关键步骤之一 隐球菌脑膜脑炎然而，关于血管内清除的知之甚少， 传播C.由于体内研究的技术挑战，特别是， 我们的理解仍然是：是否存在一种机制来积极消除传播C。新生 从脉管系统中分离出来，其机制是什么肝脏位于动脉和静脉的汇合处 血枯否细胞（KCs）占全身组织巨噬细胞的约90%， 约占总肝细胞群的15%。CRIg是一种独特的补体受体，最近已被鉴定为 人类和动物的KC。虽然肝脏不是隐球菌病的靶器官，但我们假设， 根据我们的初步数据，KCs在传播C.新生儿外出 通过涉及补体受体CRIg的机制。我们将通过以下方式来检验这一假设： 使用活体显微镜和其他先进方法实现以下目标：（1） 表征KC在过滤C中的作用。新生儿;（2）解剖机制 参与捕获传播C. KC的新型人。这项研究的结果表明， 一种旨在增强肝脏中巨噬细胞募集和活性的治疗策略可能有助于 降低艾滋病患者患隐球菌脑膜炎的风险。