The role of neutrophils in the age-driven decline in anti-pneumococcal vaccine responses

中性粒细胞在年龄驱动的抗肺炎球菌疫苗反应下降中的作用

• 批准号: 10209125
• 负责人: Elsa Bou Ghanem
• 金额: $ 29.11万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10209125
• 关键词: Affect; Age; Aging; Anti-Bacterial Agents; Antibodies; Antibody Formation; Antibody Response; Antigen-Presenting Cells; Automobile Driving; B-Lymphocytes; Bacteria; Bacterial Pneumonia; CD4 Positive T Lymphocytes; Cell physiology; Cells; Clinical; Coculture Techniques; Communities; Data; Economic Burden; Elderly; Future; Goals; Host Defense; Host resistance; Human; Human Volunteers; Immune; Immune Sera; Impairment; In Vitro; Individual; Infection; Innate Immune Response; Link; Measures; Mediating; Mediator of activation protein; Memory; Mission; Mus; Natural Immunity; Pathway interactions; Phenotype; Play; Pneumococcal Infections; Pneumococcal conjugate vaccine; Pneumococcal vaccine; Pneumonia; Population; Predisposition; Prevnar; Role; Shapes; Site; Streptococcus pneumoniae; T cell response; T-Lymphocyte; Testing; Time; Vaccinated; Vaccination; Vaccines; Work; adaptive immunity; age group; age related; aged; antimicrobial; clinically relevant; community acquired pneumonia; design; efficacy evaluation; health economics; healthy aging; immunosenescence; in vivo; innovation; mouse model; neutrophil; novel; pathogen; recruit; response; transcriptome sequencing; vaccine access; vaccine efficacy; vaccine response

ABSTRACT Despite the availability of vaccines, Streptococcus pneumoniae (pneumococcus) infections in the elderly remain a health and economic burden in the USA. This calls for a better understanding of pathways driving immune dysregulation in aged hosts, reducing vaccine efficacy and rendering this population susceptible to infections. Our long-term goal is to elucidate the role of polymorphonuclear leukocytes (PMN) in the age- driven reduction in vaccine responses and increased susceptibility to S. pneumoniae infection. Background: A key immune cell following S. pneumoniae infection is PMN. PMNs are innate cells required for controlling bacterial numbers and whose function is known to decline with age. Recent work shows that PMNs are important regulators of adaptive immunity. However, the role of PMNs in clinically relevant vaccinations and their impact in the reduced vaccine efficacy seen in aging remains completely unexplored. We found that vaccination with the pneumococcal conjugate vaccine Prevnar-13, failed to protect old mice against pneumococcal infection. Further, in young hosts, optimal protection following vaccination required PMNs both at the time vaccine administration and at the time of pneumococcal-challenge, highlighting the role of PMNs as both inducers and effectors of vaccine responses. This led to the Hypothesis that age-driven changes in PMNs result in the decline of vaccine efficacy against S. pneumoniae in the elderly. Here we test this hypothesis in both murine models and human volunteers with the following Aims: 1) Test the role of PMNs as effectors in the decline of pneumococcal vaccine efficacy during aging. 2) Test the role of PMNs as inducers of the age-driven decline in pneumococcal vaccine efficacy. 3) Test the effect of host aging on PMN responses following vaccination in human donors. Significance/ innovation: Elucidating the role of PMNs in the decline in vaccine efficacy against pneumococci in the elderly will vastly contribute to our understanding of how aging alters innate immune responses and how innate immunity in turn regulates the decline in adaptive memory responses. Further, understanding the role of PMNs, which are involved in host defense against multiple pathogens, is imperative for future design of better preventative approaches against pneumococci and other relevant infections that target the vulnerable elderly population. This proposal is perfectly in line with NIA’s mission to promote healthy aging.

抽象的 尽管有疫苗，老年人中的肺炎链球菌（肺炎球菌）感染 仍然是美国的健康和经济负担，这需要更好地了解驾驶途径。 老年宿主的免疫失调，降低疫苗功效并使该人群容易受到感染 我们的长期目标是阐明多形核白细胞（PMN）在年龄-感染中的作用。 导致疫苗反应减少和对肺炎链球菌感染的易感性增加背景： 肺炎链球菌感染后的关键免疫细胞是中性粒细胞 (PMN)，它是控制肺炎链球菌所需的先天细胞。 最近的研究表明，PMN 的细菌数量和功能会随着年龄的增长而下降。 然而，PMNs 在临床相关疫苗接种和疫苗接种中的作用。 我们发现，它们对衰老过程中疫苗功效降低的影响尚未完全探索。 接种肺炎球菌结合疫苗 Prevnar-13，未能保护老年小鼠免受感染 此外，在年轻宿主中，疫苗接种后的最佳保护需要 PMN。 在疫苗接种时和肺炎球菌攻击时，强调 PMN 的作用 疫苗反应的诱导者和效应者这导致了以下假设：年龄驱动的变化。 PMN 会导致老年人肺炎链球菌疫苗功效下降。我们对此进行了测试。 在小鼠模型和人类志愿者中提出假设，目的如下：1）测试 PMN 的作用： 衰老过程中肺炎球菌疫苗功效下降的效应物 2) 测试 PMN 作为诱导物的作用。 年龄驱动的肺炎球菌疫苗功效下降 3) 测试宿主衰老对 PMN 反应的影响。 人类捐赠者接种疫苗后的意义/创新：阐明 PMN 在下降中的作用。 老年人肺炎球菌疫苗功效的研究将极大地有助于我们了解衰老是如何发生的 改变先天免疫反应以及先天免疫如何调节适应性记忆的下降 此外，了解 PMN 的作用，它参与宿主对多种病毒的防御。 病原体，对于未来设计针对肺炎球菌和其他疾病的更好的预防方法至关重要 该提案完全符合NIA的建议。 促进健康老龄化的使命。