The impact of senescence on immune memory

衰老对免疫记忆的影响

• 批准号: 10646811
• 负责人: Laura Haynes
• 金额: $ 45.32万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-09-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646811
• 关键词: Adult; Aging; Alzheimer' s Disease; Antibodies; Antibody Affinity; Antibody Formation; Automobile Driving; Body Weight decreased; C57BL/6 Mouse; CD8-Positive T-Lymphocytes; COVID-19; Cause of Death; Cell Aging; Cells; Chronology; Clinical Trials; Communicable Diseases; DNA; Development; Disease; Elderly; Experimental Models; Failure; Functional disorder; Future; Generations; Genetic Transcription; Goals; Growth; Homeostasis; Immune response; Immune system; Immunity; Immunologic Memory; Impairment; Individual; Infection; Inflammatory; Influenza; Lung; Malignant Neoplasms; Measures; Memory; Modality; Modeling; Monitor; Mus; Pathology; Pharmaceutical Preparations; Phase; Phenotype; Play; Population; Primary Infection; Process; Reporter; Research Personnel; Risk; Role; SARS-CoV-2 infection; Serum; Shapes; T-Lymphocyte; Testing; Tissues; Transgenic Mice; Vaccination; Viral Load result; Virus; adaptive immune response; age related; aged; anti-influenza; bone health; chemokine; cytokine; disability; effector T cell; experience; flu; improved; improved outcome; influenza infection; mouse model; prevent; programs; response; senescence; single-cell RNA sequencing; stressor; transcriptomics; wound healing

PROJECT SUMMARY It is well known that age-related changes in the immune system contribute to declines in the ability to mount a highly protective response following either infection or vaccination. While vaccination does improve the outcome of influenza (flu) infection in older adults, it is still foremost among all infectious diseases causing death and disability in this population. Importantly, aging impacts almost every aspect of the adaptive immune response to influenza including generation of virus-specific CD4 and CD8 T cell effectors, high affinity antibody production and generation of protective immune memory. One of the most prominent features of aging is the accumulation of senescent cells (SC) in various tissues and in this project, we will explore the role of SC in shaping the generation of protective immune memory following influenza infection. Cellular senescence is characterized by irreversible growth arrest that occurs when cells experience a stressor. Senescence has two main roles in an adult: one is to suppress cells that have incurred DNA or other damage to prevent them from transitioning into cancer, the other is to aid in wound healing. While SC are efficiently cleared by the immune system in young individuals, this is not the case as we get older. With chronological aging, the number of senescent cells increases, resulting in many age-related pathologies and diseases. In addition, factors secreted by senescent cells (the Senescence Associated Secretory Phenotype, SASP) can also have a direct impact on surrounding cells driving dysfunction and misdirected differentiation. In this project, we will use two experimental models to examine the impact of SC on the immune responses generated following an influenza infection, with a focus on generation of protective immune memory. The first is the p16-Trimodality Reporter (p16-3MR) transgenic mouse model developed in the Campisi lab and the second is the treatment of aged C57BL/6 mice with senolytics. Importantly, our preliminary studies have shown that eliminating SC in aged mice prior to flu infection has a negative impact on the generation of protective immune memory. The goal of this proposal is to further explore how deleting SC in aged mice impacts immunity and the transition from the effector phase to the generation of durable protective memory. This proposal has high translational significance as clinical trials for the senolytics for infectious diseases, such as COVID-19, are already underway and it is important to determine if this treatment could impair protective memory formation and leave at-risk older adults at risk for severe reinfection.

项目摘要 众所周知，与年龄相关的免疫系统的变化有助于安装A的能力下降 感染或疫苗接种后高度保护性反应。虽然疫苗接种确实改善了结果 在老年人中流感（流感）感染中，在所有感染性疾病中仍然是最重要的，导致死亡和 该人群的残疾。重要的是，衰老几乎影响适应性免疫反应的各个方面 流感包括病毒特异性CD4和CD8 T细胞效应子，高亲和抗体的产生 并产生保护性免疫记忆。衰老最突出的特征之一是积累 在各种组织中以及在该项目中，我们将探讨SC在塑造该项目中的作用 流感感染后的保护性免疫记忆产生。 细胞衰老的特征是当细胞经历压力源时发生不可逆的生长停滞。 衰老在成年人中具有两个主要角色：一种是抑制患有DNA或其他损害的细胞 防止它们过渡到癌症，另一种是有助于伤口愈合。而SC有效清除 通过年轻人的免疫系统，随着年龄的增长，情况并非如此。随着时间顺序老化， 衰老细胞的数量增加，导致许多与年龄有关的病理和疾病。另外，因素 由衰老细胞分泌（衰老相关的分泌表型，SASP）也可以直接 对驱动功能障碍和误导分化的周围细胞的影响。 在这个项目中，我们将使用两个实验模型来检查SC对免疫反应的影响 在流感感染后产生，重点是产生保护性免疫记忆。第一个是 Campisi实验室开发的P16-三连电记者（P16-3MR）转基因小鼠模型 是用鼻溶剂治疗老化的C57BL/6小鼠。重要的是，我们的初步研究表明 流感感染前消除老年小鼠的SC对保护性免疫的产生产生负面影响 记忆。该提案的目的是进一步探索删除老年小鼠的SC如何影响免疫力和 从效应阶段过渡到耐用保护记忆的产生。该提议很高 翻译意义作为传染病的鼻孔术的临床试验，例如COVID-19，是 已经在进行中，重要的是确定这种治疗是否会损害保护性记忆的形成和 留下处于危险的老年人有严重再感染的风险。