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 新型隐球菌是一种致病真菌，每年在全世界造成181，000人死亡。 吸入C.新生儿，真菌在肺中生长;如果真菌在肺中的生长不受控制， 这种真菌可以迁移到中枢神经系统，引起致命的脑膜脑炎，特别是在免疫系统中。 包括艾滋病毒/艾滋病患者在内的受害者。隐球菌性脑膜脑炎是导致 艾滋病毒/艾滋病患者。C.新生儿必须通过血脑侵入大脑 屏障并在脑实质中复制。然而，在进入大脑后，这些入侵的真菌细胞会 遇到脑内巨噬细胞以及募集的炎性单核细胞及其衍生物。的 结果表明，C.这些单核吞噬细胞将决定 疾病的进展。因此，C.这些新生物 单核吞噬细胞是理解隐球菌发病机制的基础。到目前为止，人们知之甚少 关于C.新生儿和单核吞噬细胞在脑实质后， 穿过血脑屏障基于我们令人信服的初步数据，我们假设C。新生 进化的策略，以逃避宿主的防御和单核吞噬细胞编排真菌 发病机制以及清除率。通过采用基因工程C.新型菌株及其 重组菌株以及基因工程动物，我们将描述复杂的相互作用， 入侵C.新形式与单核吞噬细胞，并确定如何真菌逃脱宿主 在体内的大脑防御。如果成功，这些研究将揭示真菌感染机制的新见解。 致病机理和宿主-病原体相互作用，为靶向单核吞噬细胞提供科学依据 旨在抑制真菌在大脑中的生长