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

摘要 尽管有疫苗，但老年人肺炎链球菌（肺炎球菌）感染 这是美国的健康和经济负担。这就需要更好地理解驾驶的途径 老年宿主的免疫失调，降低疫苗效力，使这一群体易受 感染.我们的长期目标是阐明多形核白细胞（PMN）在年龄- 导致疫苗应答减少和对沙门氏菌的易感性增加。肺炎感染。背景资料： 一个关键的免疫细胞继S。肺炎感染是中性粒细胞。中性粒细胞是先天性细胞， 细菌数量和其功能是众所周知的下降与年龄。最近的研究表明，PMNs 重要的适应性免疫调节因子。然而，中性粒细胞在临床相关疫苗接种中的作用， 它们在老化中所见的疫苗效力降低中的影响仍然完全未被探索。我们发现 接种肺炎球菌结合疫苗Prevnar-13，未能保护老年小鼠免受 肺炎球菌感染此外，在年轻宿主中，接种疫苗后的最佳保护需要PMNs， 在接种疫苗和肺炎球菌攻毒时，强调了中性粒细胞作为 疫苗应答的诱导剂和效应剂。这导致了一个假设，即年龄驱动的变化， 中性粒细胞导致疫苗对沙门氏菌的功效下降。老年人的肺炎我们来测试一下 在小鼠模型和人类志愿者中的假设具有以下目的：1）测试PMNs作为 在老化过程中肺炎球菌疫苗效力下降的影响因素。2)测试中性粒细胞作为诱导剂的作用 年龄导致的肺炎球菌疫苗效力下降。3)测试宿主老化对PMN反应的影响 在人类捐赠者中接种疫苗后。意义/创新：阐明PMNs在下降中的作用 疫苗对老年人肺炎球菌的有效性将极大地有助于我们理解衰老是如何 改变先天免疫反应以及先天免疫如何反过来调节适应性记忆的下降 应答此外，了解PMNs的作用，这是参与主机防御多个 病原体，对于未来设计更好的预防肺炎球菌和其他病原体的方法至关重要。 针对脆弱老年人的相关感染。这一建议完全符合NIA的 促进健康老龄化的使命。

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.