Pneumonia and Alveolar Macrophage Resilience

肺炎和肺泡巨噬细胞的恢复能力

• 批准号: 9756517
• 负责人: Emad Arafa
• 金额: $ 4.5万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756517
• 关键词: Address; Adult; Age; Aging; Alveolar Macrophages; Antibody-mediated protection; Apoptosis; Bacterial Pneumonia; Biology; Blocking Antibodies; Bone Marrow; Cause of Death; Cell Separation; Cells; Cessation of life; Child; Childhood; Data; Disease; Elderly; Equilibrium; Exposure to; Gene Expression; Genetically Engineered Mouse; Health; Hematopoiesis; Hospitalization; Host Defense; Immune response; Immunity; Immunologic Memory; In Vitro; Infection; Inflammation; Interferon Gamma Receptor Complex; Interferon Type II; Investigation; Knowledge; Lung; Lung infections; Microbe; Morbidity - disease rate; Mus; Natural Immunity; Necrosis; Pathogenesis; Pathway interactions; Phenotype; Pneumococcal Infections; Pneumonia; Predisposition; Public Health; Race; Recombinant Cytokines; Recombinants; Recovery; Resolution; Respiratory Tract Infections; Rest; Role; Severities; Signal Transduction; Streptococcus pneumoniae; System; Testing; Tissues; Training; Vaccine Design; Yolk Sac; adaptive immunity; alveolar bone; arm; experience; gain of function; improved; in vivo; macrophage; memory CD4 T lymphocyte; middle age; monocyte; novel strategies; pathogen; pathogenic microbe; preservation; prevent; progenitor; recombinase-mediated cassette exchange; recruit; resilience; respiratory; response; transcriptome sequencing

Project Summary Bacterial pneumonia remains a major health burden at the two ends of the age spectrum. It is the host response to these microbes that leads to both susceptibility and pathogenesis for this disease, emphasizing the need to better understand the host response which determines the occurrence and severity of pneumonia. Alveolar macrophages (AM) are long-lived cells capable of surviving infections and inflammation, but microbes can cause programmed necrosis of AM. Countering AM death decreases pneumonia severity, suggesting that this AM response is a lynchpin of lung defense. Dying AM are replaced by the local proliferation of yolk sac-derived AM plus the recruitment of bone marrow-derived monocytes which differentiate into AM. Distinctive biology of these 2 AM subsets is an important knowledge gap. Recovery from previous respiratory infections remodels lung immunity to make pneumonia less likely, involving several arms of adaptive and innate immunity that are beginning to be elucidated. Whether and how AM are altered in these previously infected and now protected lungs has not been examined. We hypothesize that recovery from previous respiratory infections remodels the pool of AM and increases resilience against microbe-induced programmed necrosis. We have collected preliminary data which support this central hypothesis and guide further investigation. We will examine our central hypothesis by pursuing the following specific aims: (1) To test the hypothesis that recovery from previous respiratory infections tilts the balance of yolk sac progenitor- vs. bone marrow hematopoiesis-derived AM in the lung, followed by distinctive responses of these 2 AM sub-types when those experienced lungs get infected. (2) To test the hypothesis that IFN-γ renders alveolar macrophages more resilient. These aims will be approached using combinations of genetically engineered mice, blocking antibodies, recombinant cytokines, cell sorting, and RNAseq analyses. Elucidating what dictates macrophage resilience and finding ways to interfere with pathogen-induced macrophage programmed cell death will be steps towards new approaches for preserving macrophages to promote lung health and prevent pneumonia, to recognizing and potentially circumventing the natural loss of tissue resilience that accompanies aging, and to improving vaccine design to extend beyond antibody-mediated protection.

项目摘要 在年龄谱的两端，细菌性肺炎仍然是主要的健康伯嫩。这是 宿主对这些微生物的反应，这既导致易感性和发病机理 疾病，强调需要更好地理解宿主反应的必要 肺炎的发生和严重程度。肺泡巨噬细胞（AM）是能够长寿命的细胞 生存感染和感染，但微生物可能导致AM的编程坏死。 反击Am死亡降低了肺炎的严重程度，表明这种反应是 肺防御的Lynchpin。垂死的AM被蛋黄囊的局部扩散所取代 AM加上分化为AM的骨髓衍生的单核细胞的募集。 这2 AM子集的独特生物学是一个重要的知识差距。从 以前的呼吸道感染重塑肺免疫学使肺炎的可能性降低，涉及 自适应和先天免疫的几个臂开始阐明。是否和 这些先前感染的且现在受保护的肺的改变是如何改变的 检查。我们假设从以前的呼吸道感染中恢复会重塑池 AM和增加了针对微生物诱导的编程坏死的弹性。我们有 收集了支持此中心假设并指导进一步研究的初步数据。 我们将通过追求以下特定目的来研究我们的中心假设：（1）测试 假设从以前的呼吸道感染中恢复倾斜蛋黄的平衡 祖细胞 - 骨髓造血源自肺中的AM，其次是独特的 当这些经历的肺部感染时，这两种亚型的反应。 （2）测试 假设IFN-γ使肺泡巨噬细胞更具弹性。这些目标将是 使用一般工程小鼠的组合接近，阻止抗体， 重组细胞因子，细胞分选和RNASEQ分析。阐明什么决定 巨噬细胞的弹性并找到干扰病原体诱导巨噬细胞的方法 程序性细胞死亡将是迈向保存巨噬细胞的新方法的步骤 促进肺部健康并防止肺炎，识别并可能规避 涉及衰老的组织弹性的自然丧失，并将疫苗设计提高到 超越抗体介导的保护。