Brain dissemination of Cryptococcus neoformans mediated by neutrophils

中性粒细胞介导的新型隐球菌的脑传播

• 批准号: 8808266
• 负责人: Meiqing Shi
• 金额: $ 22.8万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8808266
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Animals; Biological Models; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; Cause of Death; Cells; Central Nervous System Infections; Cessation of life; Cryptococcus neoformans; Cryptococcus neoformans infection; Data; Development; Disease; Encapsulated; Endothelial Cells; Endothelium; Event; Exocytosis; Future; Goals; HIV; Hematogenous; Human; Immunocompromised Host; In Vitro; Individual; Infection; Invaded; Knowledge; Leukocytes; Life; Longevity; Lung; Mediating; Meningoencephalitis; Mission; Modeling; Mus; Nonlytic; Organ Transplantation; Organism; Pathogenesis; Patients; Phagocytes; Phagocytosis; Pneumonia; Prevention; Process; Recruitment Activity; Research; Respiratory System; Respiratory tract structure; Saccharomycetales; Site; Soil; Stream; Testing; Therapeutic; Therapeutic immunosuppression; Transplant Recipients; Vascular Endothelial Cell; Work; Yeasts; base; fungus; in vitro Model; in vivo; insight; intravital microscopy; migration; mouse model; neutrophil; novel; novel strategies; pathogen; peripheral blood; protective effect; public health relevance; transcytosis

DESCRIPTION (provided by applicant): Cryptococcus neoformans is an encapsulated budding yeast that causes a life-threatening illness in immunocompromised individuals, such as patients with AIDS, organ transplant recipients, and those treated with immunosuppressive therapies. Although the infection starts in the lung, cryptococcosis commonly presents as meningoencephalitis, which is one of the most common infections of the central nervous system and the leading cause of death in HIV-infected individuals. Hematogenous dissemination of C. neoformans from the lung to the brain is believed to be the most critical step in the progression of cryptococcal meningoencephalitis. How it happens, however, remains poorly understood because of the technical challenge of in vivo studies. C. neoformans is a facultative intracellular pathogen that can survive in phagocytes. Our preliminary study has provided direct evidence that C. neoformans is engulfed in the lung and subsequently disseminate to the blood within phagocytes. As neutrophils are the most abundant phagocytes in the bloodstream and have been shown to be recruited to the infected lung for phagocytosis of the yeast cells, we have developed a novel in vivo phagocytosis model to study the migration of neutrophils containing ingested C. neoformans using intravital microscopy. Based on our preliminary data showing that considerable numbers of neutrophils containing C. neoformans roll/crawl and adhere to brain vasculature after infection, we hypothesize that neutrophils mediate brain dissemination of C. neoformans by nonlytic exocytosis of the fungus and direct cell-to-cell spread of the intracellular fungus from adherent infected neutrophils to endothelial cells in the brain vasculature. We will test the hypothesis in vitro as well as in vivo by addressing the following aims using intravital microscopy and other advanced approaches: (1) Investigate migration of neutrophils harboring ingested C. neoformans from the lung to the brain vasculature; (2) Characterize nonlytic exocytosis of C. neoformans by neutrophils and the BBB crossing of the yeast cells via a direct cell-to-cell spread from adherent infected neutrophils to endothelial cells in the brain vasculature. The proposed studies will provide unique insights into brain dissemination of C. neoformans, facilitating the development of novel prevention and therapeutic strategies.

描述(申请人提供)：新生隐球菌是一种被包裹的芽生酵母菌，在免疫功能受损的人中会导致危及生命的疾病，如艾滋病患者、器官移植接受者和那些接受免疫抑制治疗的人。虽然感染始于肺部，但隐球菌病通常表现为脑膜脑炎，这是最常见的中枢神经系统感染之一，也是艾滋病毒感染者的主要死亡原因。从肺到脑的血源性传播被认为是隐球菌性脑膜脑炎进展过程中最关键的一步。然而，由于活体研究的技术挑战，它是如何发生的仍然知之甚少。新生葡萄球菌是一种兼性胞内细菌。 能在吞噬细胞中存活的病原体。我们的初步研究提供了直接证据，证明新生葡萄球菌被吞噬在肺内，随后在吞噬细胞内扩散到血液中。由于中性粒细胞是血流中最丰富的吞噬细胞，并已被证明被招募到感染肺吞噬酵母菌细胞，我们发展了一种新的体内吞噬模型，利用活体显微镜研究含有吞噬新生葡萄球菌的中性粒细胞的迁移。根据我们的初步数据显示，感染后有相当数量的中性粒细胞滚动/爬行并附着在脑血管系统上，我们假设中性粒细胞通过真菌的非溶血性胞吐和细胞内细胞间的直接扩散来介导新生葡萄球菌的脑传播。 真菌从粘附性感染的中性粒细胞到脑血管内皮细胞。我们将通过使用活体显微镜和其他先进方法在体外和体内验证这一假说，以达到下列目标：(1)调查携带摄入的新生葡萄球菌的中性粒细胞从肺到脑血管的迁移；(2)研究中性粒细胞对新生葡萄球菌的非溶血性排泄作用；(2)研究酵母细胞通过贴壁感染的中性粒细胞向脑血管内皮细胞的直接细胞对细胞传播的BBB跨越。拟议的研究将为新生隐球菌脑传播提供独特的见解，促进新的预防和治疗策略的发展。