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，并可能加剧组织损伤 和疾病进展。老年人患有“炎症”，即基础和 诱导的促炎细胞因子水平。此外，来自老年人的多形核白细胞（PMNs） 个体在几种活动中表现出缺陷，如趋化性、调理吞噬杀伤和ROS 生产使用野生型小鼠的肠道内攻击模型，该模型概括了对 在老年人肺炎球菌感染中，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PMNs赋予了对肺炎球菌肺攻击的抵抗力，表明 年轻的PMNs具有老年PMNs所缺乏的防御功能。比较基因表达， 未感染或暴露于肺炎球菌的年轻和老年小鼠的中性粒细胞（由我们的合作者Bou Ghanem博士提供） 显示了年龄依赖性表达差异。然而，导致年龄增长的确切的PMN功能障碍- 依赖性易感性仍然是未知的，并且是该提议的焦点。在这里，我们建议确定 特定的PMN功能，随着年龄的增长而减少，导致对肺炎球菌肺部感染的易感性， 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 降低的防御和/或增强的疾病促进活性。通过精确定位关键的宿主防御， 随着年龄的增长而降低，并导致侵袭性肺炎球菌疾病，这些研究不仅有助于精确地 针对主要传染源的有针对性的干预措施，还可以深入了解先天免疫老化 该系统可能会产生针对其他不成比例地困扰老年人的感染的新疗法。在 此外，我们采用高风险、高回报的方法，寻求治疗来自HoxB 8祖细胞的PMNs 在老年宿主的血流中发现具有低水平的炎性细胞因子的细胞系， 中性粒细胞的活性和RNA表达与衰老表型有关.我们的目标是（1） 表征衰老时减少的PMN功能，并重现这些PMN缺陷， 永生化的骨髓祖细胞。(2)评估老年PMN不仅不能防御 感染，但也积极促进肺炎球菌疾病，从而有助于与年龄相关的易感性， S.肺炎。