Interaction of Human Pulmonary Macrophage and Dendritic Cell Subsets with Cryptococcus neoformans

人肺巨噬细胞和树突状细胞亚群与新型隐球菌的相互作用

• 批准号: 10341207
• 负责人: Karen Lynn Wozniak
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10341207
• 关键词: Acquired Immunodeficiency Syndrome; Adopted; Alveolar Macrophages; Antifungal Agents; Brain; Bronchoalveolar Lavage; Cathepsins B; Cells; Cessation of life; Characteristics; Cryptococcus; Cryptococcus neoformans; Data; Dendritic Cells; Enzymes; Exhibits; Flow Cytometry; Fluorescence Microscopy; Future; Gene Expression Profile; Genes; Genetic Transcription; Growth; Human; Human Activities; Immunity; Immunotherapeutic agent; Individual; Industrial fungicide; Inhalation; Integration Host Factors; Intervention; Knowledge; Life; Lung; Mediator of activation protein; Meningitis; Monitor; Morphology; Neuraxis; Oklahoma; Organism; Outcome; Pathogenesis; Pathway interactions; Phagocytes; Phagosomes; Production; Role; Shapes; Signal Pathway; Signal Transduction Pathway; Testing; Time; Tissue-Specific Gene Expression; cell killing; daughter cell; inhibitor; macrophage; microbial; novel; pathogen; pathogenic fungus; prevent; response; transcriptome sequencing

Cryptococcus neoformans meningitis occurs in approximately 225,000 individuals with AIDS each year, resulting in over 181,000 annual deaths. C. neoformans is an opportunisitic fungal pathogen that is inhaled and subsequently escapes the lungs and disseminates to the central nervous system where life-threatening meningitis occurs. Host factors that determine whether C. neoformans initially survives or is destroyed by pulmonary phagocytes remain poorly defined, presenting a major gap in understanding how this pathogen ultimately causes meningitis and death. It is postulated that C. neoformans uses macrophages for transport from the lung to the brain to cause meningitis. However, C. neoformans can be killed in some macrophages but replicates in others. In addition, we and others have shown that dendritic cells (DCs), a critical innate phagocyte in the lung, can engulf and destroy C. neoformans, but like macrophages this may be restricted to a subset of DCs. Our preliminary data indicate subsets of primary human pulmonary macrophages and DCs interact with C. neoformans and exhibit differential anti-cyptococcal activities. Some innate phagocyte subsets kill C. neoformans, and others do not. Therefore, we hypothesize that subsets of innate phagocytes in the lung are capable of restricting C. neoformans growth through direct intracellular fungicidal activity absent in permissive subsets of DCs and macrophages. We will monitor and characterize the fungicidal response of human pulmonary phagocyte subsets to C. neoformans and then examine roles of mediators of fungicidal activity (iNOS, ROS, and lysosomal enzyme cathepsin B) in each subset (Aim 1). Next, we will identify differentially regulated genes and signaling pathways that may coordinate fungicidal activity in each subset following interaction with C. neoformans (Aim 2). Consequently, our studies will identify phagocyte subsets responsible for anti-cryptocccal activity or permissive fungal growth and identify the host genes and signaling pathways that may be responsible for regulating these responses.

每年约有 225,000 名艾滋病患者发生新型隐球菌脑膜炎，导致 每年死亡人数超过 181,000 人。新型隐球菌是一种机会性真菌病原体，可通过吸入和 随后逸出肺部并传播到中枢神经系统，危及生命 发生脑膜炎。决定新型隐球菌最初存活还是被破坏的宿主因素 肺吞噬细胞的定义仍然不明确，在理解这种病原体如何 最终导致脑膜炎和死亡。据推测，新型隐球菌使用巨噬细胞从 肺到脑引起脑膜炎。然而，新型隐球菌可以在某些巨噬细胞中被杀死，但 在其他人身上复制。此外，我们和其他人已经证明，树突状细胞（DC）是一种关键的先天吞噬细胞 在肺部，可以吞噬并破坏新型隐球菌，但与巨噬细胞一样，这可能仅限于 DC。我们的初步数据表明原代人肺巨噬细胞和 DC 的子集与艰难梭菌相互作用。 新型隐球菌并表现出不同的抗隐球菌活性。一些先天吞噬细胞亚群杀死 C. 新型隐球菌，而其他人则没有。因此，我们假设肺中先天吞噬细胞的子集 能够通过直接的细胞内杀菌活性来限制新型隐球菌的生长 DC 和巨噬细胞的许可子集。我们将监测和表征杀菌反应 人肺吞噬细胞亚群对新型隐球菌的影响，然后检查杀菌活性介质的作用 （iNOS、ROS 和溶酶体酶组织蛋白酶 B）在每个子集中（目标 1）。接下来我们来区别识别 调节的基因和信号通路可以协调以下每个子集中的杀菌活性 与新型隐球菌相互作用（目标 2）。因此，我们的研究将确定负责的吞噬细胞亚群 用于抗隐球菌活性或允许真菌生长，并确定宿主基因和信号通路 可能负责调节这些反应。