The role of A1 adenosine receptor signaling in the decline of S. pneumoniae killing by neutrophils in vaccinated aged hosts

A1 腺苷受体信号传导在疫苗接种老年宿主中中性粒细胞杀伤肺炎链球菌下降中的作用

• 批准号: 10605737
• 负责人: Shaunna Simmons
• 金额: $ 3.32万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605737
• 关键词: Academia; Adenosine; Adenosine A1 Receptor; Adult; Affect; Age; Aging; Anti-Bacterial Agents; Antibacterial Response; Antibodies; Automobile Driving; Bacteria; Cell surface; Cells; Cellular biology; Cessation of life; Complement; Complement Receptor; Cytoplasmic Granules; Data; Defect; Deposition; Elderly; Environment; Exposure to; Fc Receptor; Future; Goals; Gram-Positive Bacteria; Host Defense; Host resistance; Human; Immune; Immune Sera; Immune response; Immunize; Immunology; Impairment; Infection; Innate Immune System; Knowledge; MAP Kinase Gene; MAPK3 gene; Mediating; Mentors; Microscopy; Mus; Opsonin; Pathway interactions; Phagocytosis; Phagosomes; Pneumococcal Infections; Pneumococcal conjugate vaccine; Pneumococcal vaccine; Predisposition; Prevnar; Production; Purinergic P1 Receptors; Qualifying; Receptor Signaling; Research; Research Training; Resistance; Resources; Role; Science; Signal Pathway; Signal Transduction; Streptococcus pneumoniae; Surface; Technical Expertise; Techniques; Testing; Time; Training; Universities; Vaccinated; Vaccination; Vaccines; Vulnerable Populations; Work; age related; aged; antimicrobial; bacterial community; bactericide; career; cell injury; community acquired pneumonia; design; extracellular; human old age (65+); immune function; immune system function; immunosenescence; improved; medical schools; neutrophil; pathogen; receptor; recruit; response; therapeutic target; transcriptome sequencing; uptake; vaccine efficacy

Streptococcus pneumoniae (pneumococcus) are Gram-positive bacteria responsible for 1.6 million deaths globally each year. Available pneumococcal vaccines have reduced efficacy in the elderly, and despite vaccination, S. pneumoniae remain the leading cause of bacterial community-acquired pneumonia in adults over the age of 65. This decline in vaccine efficacy is driven by immunosenescence, the age-associated decline in immune function. Polymorphonuclear leukocytes (PMNs) are cells of the innate immune system and are required for host defense against S. pneumoniae infection. PMNs isolated from aged hosts display a significant reduction in pneumococcal killing when compared to PMNs from young hosts. This reduction in killing persists despite opsonization of bacteria with specific anti-pneumococcal antibodies, however, the signaling pathways driving this decline in PMN function and the role of PMNs in the age-related reduction in vaccine efficacy remain unclear. One pathway that controls PMN antibacterial responses is the extracellular adenosine pathway but the role of this pathway in vaccinated hosts and how it changes with age remain unexplored. This led to the hypothesis that with age, there is a decline in intracellular bacterial killing following antibody mediated uptake of S. pneumoniae, which is driven by changes in adenosine receptor signaling. This hypothesis will be tested using two specific aims: 1) Identify why intracellular killing of S. pneumoniae is defective in PMNs from old mice and 2) Identify the role of adenosine receptor signaling in the age-driven decline in intracellular killing of S. pneumoniae by PMNs. This project is significant as it will identify the mechanism of the age-related changes in PMN function following antibody mediated uptake of S. pneumoniae. Additionally, PMNs are involved in host defense against multiple pathogens, therefore this work may provide a potential therapeutic target to boost overall vaccine protectiveness in aged hosts. The overall goal of this research training plan is to strengthen the candidate’s knowledge in host-pathogen interactions, immunology, and immunosenescence. As well as to advance technical skills in microscopy, signaling, and cell biology techniques. These aims and goals will be accomplished with the guidance of the qualified mentoring team assembled by the candidate and will be aided by the opportunities offered by the training environment at the University at Buffalo Jacobs School of Medicine and Biomedical Sciences. These resources will provide the necessary training and support to complete the proposed research and guide the candidate’s future career in academia.

肺炎链球菌（肺炎球菌）是革兰氏阳性细菌，造成160万人死亡 每年全球。可用的肺炎球菌疫苗的效率降低了，多矿 疫苗接种，肺炎链球菌仍然是细菌社区获得性肺炎的主要原因 65岁。疫苗效率的下降是由免疫衰老驱动的，与年龄相关的下降 免疫功能。多形核白细胞（PMN）是先天免疫系统的细胞，需要 用于针对肺炎链球菌感染的宿主防御。从老年宿主分离的PMN显示显着降低 与年轻宿主的PMN相比，在肺炎球菌杀死中。杀戮的减少持续存在 但是，细菌用特定的抗链球菌抗体进行调整，但是，驱动的信号通路 PMN功能的下降以及PMN在疫苗效率与年龄相关的降低中的作用尚不清楚。 控制PMN抗菌反应的一种途径是细胞外腺苷途径，但 接种接种宿主的这一途径及其如何随着年龄的变化而变化。这导致了假设 随着年龄的增长，抗体介导的S. 肺炎是由腺苷受体信号传导变化驱动的。该假设将使用 两个具体的目的：1）确定为什么细胞内肺炎链球菌在旧鼠的PMN中有缺陷， 2）确定腺苷接收器信号传导在年龄驱动的S.细胞内杀死中的作用。 PMNS的肺炎。该项目很重要，因为它将确定与年龄相关变化的机制 抗体介导的肺炎链球菌摄取后的PMN功能。此外，PMN涉及主机 针对多种病原体的防御，因此这项工作可能会提供潜在的治疗靶点来提升 老年宿主的总体疫苗保护。该研究培训计划的总体目标是加强 候选人在宿主 - 病原体相互作用，免疫学和免疫衰老方面的知识。以及 提高了显微镜，信号传导和细胞生物学技术方面的技术技能。这些目标和目标将是 在由候选人组成的合格指导团队的指导下完成的，将得到帮助 根据布法罗·雅各布斯医学院大学培训环境提供的机会 和生物医学科学。这些资源将提供必要的培训和支持，以完成 拟议的研究和指导候选人在学术界的未来职业。