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 新生隐球菌是一种致病真菌，每年在全球范围内造成181,000人死亡。 吸入新生芽孢杆菌后，真菌会在肺部生长；如果肺部的真菌生长得不到控制， 这种真菌可以迁移到中枢神经系统，导致致命的脑膜脑炎，特别是在免疫系统中。 受影响的个人，包括艾滋病毒/艾滋病患者。隐球菌性脑膜脑炎是 艾滋病毒/艾滋病患者。要引起脑膜脑炎，新生葡萄球菌必须通过血脑侵入大脑。 在脑实质中形成屏障并复制。然而，在进入大脑后，这些入侵的真菌细胞将 遇到脑内滞留的巨噬细胞，以及招募炎性单核细胞及其衍生物。这个 新生弧菌与这些单核巨噬细胞相互作用的结果将决定 疾病的发展。因此，新生葡萄球菌与这些细菌相互作用的机制 单核巨噬细胞是了解隐球菌发病机制的基础。到目前为止，人们对此知之甚少 新生葡萄球菌与脑实质单核巨噬细胞相互作用的研究 穿过血脑屏障。根据我们令人信服的初步数据，我们假设新生葡萄球菌 逃避宿主防御和单核吞噬细胞协调真菌的进化策略 病机和清除。通过使用基因工程的新生葡萄球菌菌株和他们的 重组菌株和基因工程动物，我们将描述复杂的相互作用 用单核吞噬细胞入侵新生隐孢子虫，并确定真菌如何逃离宿主 在体内大脑中的防御。如果成功，这些研究将揭示对真菌机制的新见解 发病机制和宿主-病原体相互作用，为靶向单核巨噬细胞提供科学依据 旨在抑制大脑中的真菌生长。