Pneumonia and Alveolar Macrophage Resilience

肺炎和肺泡巨噬细胞的恢复能力

• 批准号: 9921207
• 负责人: Emad Arafa
• 金额: $ 4.55万
• 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/9921207
• 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 细菌性肺炎仍然是年龄段的两端的主要健康负担 宿主对微生物的反应，导致敏感性和发病机理 疾病，强调需要更好地确定您的宿主反应 肺炎的发生和严重程度。 幸存的感染和炎症，但微生物可能导致AM的编程坏死。 反抗AM死亡降低了肺炎的严重程度，表明这种AM反应是 肺部防御的林奇宾被当地繁殖所取代。 AM加上分化为AM的骨髓衍生的单核细胞的募集。 2 AM子集的独特生物学是一个不受欢迎的差距 以前的呼吸感染重塑肺免疫使肺炎的可能性降低，涉及 适应性和先天免疫的几个武器是阐明的 在这些先前感染和现在受保护的肺部中如何采取动脉 检查了。 AM并增加了对微生物诱导的编程坏死的弹性 收集的初步数据支持中央假设并指导进一步的投资。 我们将通过追求以下特定目的来检查我们的中心假设：（1）测试您 假设从先前的呼吸中恢复蛋黄囊倾斜 祖细胞 - 骨髓造血源自肺中的AM，其次是独特的 这2个AM类型的反应当Texperience肺部感染时（2）。 假设IFN-γ使肺泡巨噬细胞更具弹性。 使用遗传发动机小鼠的组合来接近，阻止抗体， 重组细胞因子，细胞分选和RNASEQ分析。 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，采取了迈向新方法的步骤 促进肺部健康和肺炎，以识别并可能对您进行表达 组织弹性的自然丧失伴随衰老的自然丧失，并将疫苗设计改善为 超越抗体介导的保护。