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

摘要 尽管有疫苗可用，但老年人中肺炎链球菌(肺炎球菌)感染 在美国仍然是一个健康和经济负担。这就需要更好地理解驾驶路径。 老年宿主的免疫失调，降低疫苗效力，使这一人群容易患上 感染。我们的长期目标是阐明多形核白细胞(PMN)在老年- 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。中性粒细胞是先天细胞，需要控制 细菌的数量和功能已知随着年龄的增长而下降。最近的研究表明，PMN是 适应性免疫的重要调节因子。然而，中性粒细胞在临床相关疫苗接种和 它们在衰老过程中疫苗效力降低方面的影响仍完全未被探索。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PMN 在疫苗接种和肺炎球菌挑战时，突出了PMN的作用 疫苗反应的诱导者和效应者。这导致了一种假设，即年龄驱动的变化 中性粒细胞导致老年人肺炎链球菌疫苗效力下降。在这里我们测试一下这个 在小鼠模型和人类志愿者中的假说，目的如下：1)测试PMN作为 肺炎球菌疫苗效力在老化过程中的下降。2)测试PMN作为诱导者的作用 肺炎球菌疫苗效力的年龄驱动下降。3)测试宿主老化对PMN响应的影响 在人类捐赠者接种疫苗后。意义/创新：阐明PMN在下降中的作用 疫苗对老年人肺炎球菌的疗效将极大地有助于我们了解衰老 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 回应。此外，了解PMN的作用，PMN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 以弱势老年人口为目标的相关感染。这项建议与NIA的建议完全一致 倡导健康老龄化的使命。

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.