Interactions of Cryptococcus neoformans with mononuclear phagocytes in the brain

新型隐球菌与大脑中单核吞噬细胞的相互作用

• 批准号: 10667732
• 负责人: Meiqing Shi
• 金额: $ 19.17万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-19 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10667732
• 关键词: Accounting; Animal Model; Animals; Autopsy; Blood; Blood - brain barrier anatomy; Bone Marrow; Brain; Cell Communication; Cells; Central Nervous System; Cessation of life; Clinical; Clinical Data; Complex; Cre lox recombination system; Cryptococcosis; Cryptococcus; Cryptococcus neoformans; Cryptococcus neoformans infection; Data; Dendrites; Dendritic Cells; Disease; Disease Progression; Effector Cell; Emigrations; Exhibits; Genetic Engineering; Growth; HIV/AIDS; Host Defense; Human; ITGAM gene; Immune; Immune system; Immunocompromised Host; In Vitro; Individual; Infection; Inflammatory; Inhalation; Invaded; Life; Lung; Lung infections; Macrophage; Mediating; Meningoencephalitis; Microbe; Microglia; Mononuclear; Mus; Mycoses; Nerve; Outcome; Pathogenesis; Patients; Persons; Phagocytes; Phagocytosis; Play; Population; Publishing; Rest; Role; System; Therapeutic; Tissues; Work; Yeasts; blood-brain barrier crossing; brain parenchyma; brain tissue; fungicide; fungus; in vivo; insight; intravital microscopy; migration; monocyte; mortality; mutant; novel; pathogen; pathogenic fungus; prevent; reconstitution; recruit; therapeutic development

Project Summary Cryptococcus neoformans is a pathogenic fungus, accounting for 181,000 deaths each year, worldwide. After inhalation of C. neoformans, the fungus grows in the lung; if the fungal growth is not controlled in the lung, the fungus can migrate to the central nervous system, causing fatal meningoencephalitis, particularly in immune compromised individuals including HIV/AIDS patients. Cryptococcal meningoencephalitis is a leading cause of HIV/AIDS patients. To cause meningoencephalitis, C. neoformans must invade the brain across the blood-brain barrier and replicate in the brain parenchyma. However, after entering the brain, these invading fungal cells will encounter brain resident macrophages as well as recruited inflammatory monocytes and their derivatives. The outcome of the interactions between C. neoformans and these mononuclear phagocytes will determine the progression of the disease. Thus, the mechanism behind the interactions of C. neoformans with these mononuclear phagocytes is fundamental for understanding cryptococcal pathogenesis. So far, little is known about the interactions between C. neoformans and mononuclear phagocytes in the brain parenchyma after its crossing the blood-brain barrier. Based on our compelling preliminary data, we hypothesize that C. neoformans evolved strategies to escape from host defense and that mononuclear phagocytes orchestrate fungal pathogenesis as well as clearance. By employing genetically engineered C. neoformans strains and their reconstitute strains as well as genetically engineered animals, we will characterize the complex interactions of invading C. neoformans with mononuclear phagocytes and determine how the fungus escapes from host defense in the brain in vivo. If successful, these studies would reveal novel insights into mechanisms of fungal pathogenesis and host-pathogen interactions, providing scientific basis for targeting mononuclear phagocytes aimed at inhibiting fungal growth in the brain.

项目摘要 Neoformans是一种致病的真菌，每年在全球占181,000人死亡。 吸入Neoformans后，真菌在肺部生长。如果真菌生长在肺部不受控制， 真菌可以迁移到中枢神经系统，导致致命的脑膜炎，尤其是在免疫中 包括艾滋病毒/艾滋病患者在内的个人受损。隐脑脑膜脑炎是 艾滋病毒/艾滋病患者。为了引起脑膜脑炎，梭状芽胞杆菌必须侵入大脑 屏障并在大脑实质中复制。但是，进入大脑后，这些入侵的真菌细胞将 遇到大脑常驻巨噬细胞以及招募的炎症单核细胞及其衍生物。这 新生梭菌与这些单核吞噬细胞之间相互作用的结果将确定 疾病的进展。因此，梭菌新生虫与这些相互作用的机制 单核吞噬细胞是理解隐球菌发病机理的基础。到目前为止，鲜为人知 关于脑实质中新生梭菌与单核吞噬细胞之间的相互作用之后 越过血脑屏障。根据我们引人注目的初步数据，我们假设Neoformans 不断发展的策略以逃避宿主防御和单核吞噬细胞编排真菌 发病机理和清除。通过采用基因工程的新角菌菌株及其 重构菌株以及基因工程动物，我们将表征 用单核吞噬细胞入侵Neoformans，并确定真菌如何从宿主那里逃脱 体内大脑中的防御。如果成功，这些研究将揭示对真菌机制的新见解 发病机理和宿主 - 病原体相互作用，为靶向单核吞噬细胞提供了科学基础 旨在抑制大脑的真菌生长。