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 尽管有疫苗的可用性，但肺炎链球菌（肺炎球菌）感染较早 在美国仍然是健康和经济烧伤。这需要更好地了解驾驶路径 老年宿主的免疫失调，降低了疫苗效率并使该人群易于 感染。我们的长期目标是阐明多形核白细胞（PMN）在年龄中的作用。 疫苗反应的降低并增加了对肺炎链球菌感染的敏感性。背景： 肺炎链球菌感染后的关键免疫细胞为PMN。 PMN是控制所需的先天单元 细菌数量并且已知其功能随着年龄的增长而下降。最近的工作表明PMN是 适应性免疫学的重要调节剂。但是，PMN在临床相关疫苗中的作用和 它们对衰老中降低的疫苗效率的影响仍然完全出乎意料。我们发现 肺炎球菌结合疫苗PrevNar-13未能保护旧小鼠免受疫苗接种 肺炎球菌感染。此外，在年轻的宿主中，疫苗接种后需要PMN的最佳保护 在疫苗给药和肺炎球菌挑战时，突出了PMN的作用 影响者和疫苗反应的影响。这导致了以下假设：年龄驱动的变化 PMN会导致疫苗效率下降，而对肺炎链球菌的效率较长。在这里我们测试这个 以下目的的鼠模型和人类志愿者中的假设：1）测试PMN的作用 衰老过程中肺炎球菌疫苗有效性下降的效应子。 2）测试PMN作为影响者的作用 年龄驱动的肺炎球菌疫苗有效性下降。 3）测试宿主衰老对PMN响应的影响 在人类捐助者中进行疫苗。意义/创新：阐明PMN在下降中的作用 在对肺炎肺炎的疫苗效率方面，古老的肺炎球菌将极大地有助于我们对衰老的理解 改变先天的免疫调查以及先天免疫蛋白如何调节适应性记忆的下降 回答。此外，了解PMN的作用，PMN参与了宿主防御的反对多重 病原体是对未来对针对肺炎肺炎和其他的更好预防方法的设计。 针对脆弱的老年人群的相关感染。该提议与Nia的建议完全一致 促进健康衰老的使命。