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

• 批准号: 10152199
• 负责人: JOHN M LEONG
• 金额: $ 25.53万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152199
• 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 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

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/总结 免疫衰老，即与年龄相关的免疫功能下降，表现为易感性增加 许多传染病，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 和疾病进展。老年人患有“炎症”，即基础和炎症水平随年龄增长而增加 诱导促炎细胞因子水平。此外，来自老年人的多形核白细胞（PMN） 个体在多种活动中表现出缺陷，例如趋化性、调理吞噬杀伤和活性氧 生产。使用野生型小鼠的气管内攻击模型，该模型概括了对 对于老年人肺炎球菌感染，我们的初步数据表明PMN功能障碍可能是一个 肺炎球菌肺炎易感性增加的主要原因。此外，收养转移 从年轻小鼠到老年小鼠的 PMN 赋予了对肺炎球菌肺部攻击的抵抗力，这表明 年轻的 PMN 具有老年 PMN 所缺乏的防御功能。比较基因表达 来自年轻和老年小鼠的未感染或肺炎球菌暴露的 PMN（由我们的合作者 Bou Ghanem 博士提供） 揭示了年龄依赖性的表达差异。然而，精确的 PMN 功能障碍导致年龄 依赖性易感性仍然未知，也是本提案的重点。在这里我们建议确定 特定的 PMN 功能会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 介导的易感性在多大程度上是由于 防御能力减弱和/或疾病促进活动增强。通过查明关键的宿主防御 随着年龄的增长而降解并导致侵袭性肺炎球菌疾病，这些研究不仅将促进精确 针对主要传染源的有针对性的干预措施，同时也提供了对老化先天免疫的深入了解 该系统可能会带来针对老年人不成比例的其他感染的新疗法。在 此外，我们采取高风险、高回报的方法，寻求治疗源自 HoxB8 祖细胞的中性粒细胞 在老年宿主的血液中发现具有低水平炎症细胞因子的细胞系，以赋予这些 PMN 是有关 PMN 活性和 RNA 表达的老化表型特征。我们的目标是 (1) 描述 PMN 功能随着年龄的增长而减弱，并概括这些 PMN 中的缺陷源自 永生化骨髓祖细胞。 (2) 评估老化的 PMN 不仅无法防御的程度 感染，还会积极促进肺炎球菌疾病，从而导致与年龄相关的易感性 肺炎链球菌。