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Features of PMN Senescence that Lead to Susceptibility to Pneumococcal Infection

导致肺炎球菌感染易感性的中性粒细胞衰老特征

基本信息

批准号：
10356895
负责人：
JOHN M LEONG
金额：
$ 21.38万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10356895
关键词：
Acute Adoptive Transfer Age Aging Bacterial Genes Biological Assay Blood Blood Circulation CRISPR/Cas technology Cell Differentiation process Cell Line Cell surface Characteristics Chemotactic Factors Chemotaxis Clinical Communicable Diseases Data Defect Disease Disease Progression Eicosanoids Elderly Environment Epigenetic Process Epithelial Etiology Failure Functional disorder Gene Expression Genes Genetic Transcription Host Defense Immune Immunologics Individual Infection Infectious Agent Infiltration Inflammaging Inflammation Inflammatory Innate Immune System Interleukin-1 Intervention Lead Lung Lung infections Matrix Metalloproteinases Mediating Modeling Morphology Mus Myelogenous Phenotype Pneumococcal Infections Pneumococcal Pneumonia Predisposition Process Production Pulmonary Challenge Pulmonary Inflammation Resistance Role Serine Protease Serum Source Streptococcus pneumoniae Surface System Systemic disease TNF gene Testing Tissues Wild Type Mouse age related aged cytokine design experience genetic approach genetic manipulation genome wide screen high reward high risk immune function immunosenescence insight macrophage migration mutant neutrophil novel therapeutics progenitor senescence stem cells transcriptome sequencing

项目摘要

PROJECT ABSTRACT/SUMMARY Immunosenescence, the age-related decline in immune function, is manifested by an increase in susceptibility to many infectious diseases, including serious Streptococcus pneumoniae (pneumococcus) infection. Acute pulmonary inflammation is characteristic of pneumococcal lung infection and may exacerbate tissue damage and disease progression. The elderly suffer from `Inflammaging', the age-dependent increase in basal and induced levels of proinflammatory cytokines. Further, polymorphonuclear leukocytes (PMNs) from elderly individuals display defects in several activities, such as chemotaxis, opsonophagocytic killing, and ROS production. Using a model of intratracheal challenge of wild-type mice, which recapitulates the susceptibility to pneumococcal infection among the elderly, our preliminary data suggests that PMN dysfunction may be a primary cause of the increased susceptibility to pneumococcal pneumonia. Furthermore, adoptive transfer of PMNs from young mice into aged mice conferred resistance to pneumococcal lung challenge, indicating that young PMNs possess defense functions that are lacking in aged PMNs. Comparing the gene expression of uninfected or pneumococcus-exposed PMNs from young and aged mice (by our collaborator Dr. Bou Ghanem) revealed age-dependent expression differences. However, the precise PMN dysfunction leading to age- dependent susceptibility remains unknown and is a focus of this proposal. Here we propose to identify the specific PMN functions that diminish with age and result in the susceptibility to pneumococcal lung infection, as well as systematically test the degree to which age-associated, PMN-mediated susceptibility is due to a diminished defense and/or an enhanced disease-promoting activity. By pinpointing the key host defenses that degrade with age and result in invasive pneumococcal disease, these studies will not only facilitate precisely targeted interventions against a major infectious agent, but also provide insight into the aging innate immune system that may lead to novel therapies against other infections that disproportionately afflict the elderly. In addition, taking a high-risk, high-reward approach, we seek to treat PMNs derived from HoxB8 progenitor cell lines with low levels of inflammatory cytokines found in the bloodstream of the aged host to confer on these PMNs an aged phenotypic profile with respect to PMN activities and RNA expression. Our Aims are (1) Characterize PMN functions that diminish upon aging and recapitulation these defects in PMNs derived from immortalized myeloid progenitors. (2) Assess the degree to which aged PMNs not only fail to defend against infection but also actively promote pneumococcal disease, thus contributing to age-associated susceptibility to S. pneumoniae.

项目摘要/摘要免疫衰老是与年龄相关的免疫功能下降，表现为易感性的增加。对多种传染病，包括严重的肺炎链球菌(肺炎球菌)感染。急性肺部炎症是肺炎球菌肺部感染的特征，可能会加剧组织损伤。和疾病的进展。老年人患有‘炎症性’，与年龄相关的基础和诱导促炎细胞因子水平。此外，老年人的中性粒细胞(PMN) 个体在几种活动中表现出缺陷，如趋化、吞噬细胞杀伤和ROS 制作。使用野生型小鼠的气管内攻击模型，概括了对肺炎球菌在老年人中的感染，我们的初步数据表明PMN功能障碍可能是肺炎球菌肺炎易感性增加的主要原因。此外，收养转让从年轻小鼠到老年小鼠的PMN对肺炎球菌肺攻击具有抵抗力，表明年轻的中性粒细胞具有老年中性粒细胞所缺乏的防御功能。比较两种病毒的基因表达来自幼鼠和老年鼠的未感染或肺炎球菌暴露的PMN(由我们的合作者Bou Garem博士提供) 揭示了年龄相关的表达差异。然而，导致衰老的确切的PMN功能障碍- 依赖易感性仍不清楚，这是这项提议的一个重点。在这里，我们建议确定中性粒细胞的特定功能随着年龄的增长而减弱，并导致对肺炎球菌肺部感染的易感性，如以及系统地测试与年龄相关的PMN介导的易感性是由于抵抗力减弱和/或促进疾病的活动增强。通过精确定位关键的主机防御，随着年龄的增长而退化并导致侵袭性肺炎球菌疾病，这些研究不仅将有助于准确地针对主要感染源的有针对性的干预，也提供了对老化的先天免疫的洞察这一系统可能导致针对其他感染的新疗法，这些感染对老年人造成了不成比例的痛苦。在……里面此外，采用高风险、高回报的方法，我们寻求治疗来自HoxB8祖细胞的PMN 在老年宿主的血液中发现的炎性细胞因子水平较低的品系与这些中性粒细胞是一种关于中性粒细胞活性和RNA表达的衰老表型.我们的目标是(1) 描述PMN功能随年龄增长而减弱的特征，并概括PMN的这些缺陷永生的髓系祖细胞。(2)评估老化的PMN不仅没有防御到什么程度感染还会积极促进肺炎球菌病，从而导致与年龄相关的易感性肺炎链球菌。