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Lung-resident antibacterial heterotypic immunity

肺驻留抗菌异型免疫

基本信息

批准号：
8986378
负责人：
JOSEPH P MIZGERD
金额：
$ 40.93万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8986378
关键词：
Acute Adult Age Aging Alveolar Macrophages American Anti-Bacterial Agents Antibacterial Response Antibodies Antigens Bacteria Bacterial Pneumonia Biological Biology CD4 Positive T Lymphocytes Cause of Death Cells Cessation of life Child Childhood Clinical Collecting Cell Communicable Diseases Complement Elderly Exposure to Future Gene Expression Profile Homing Hospitalization Host Defense Human Immune Immunity Immunologic Memory Infection Inflammation Influenza Interleukin-17 Intervention Investigation Knowledge Lung Lymphocyte Lymphoid Memory Microbe Modeling Mus Natural Immunity Organ Organism Patients Phagocytes Phenotype Pneumococcal Infections Pneumonia Predisposition Property Public Health Recruitment Activity Research Respiratory System Respiratory tract structure Sampling Secondary to Signal Transduction Streptococcus pneumoniae Structure of parenchyma of lung T memory cell Testing Time Tissues Vaccination Vaccine Design adaptive immunity age related aged arm base early childhood empowered falls high risk human subject improved insight memory CD4 T lymphocyte microbial mouse model neutrophil novel novel strategies novel therapeutic intervention pathogen prevent public health relevance respiratory response young adult

项目摘要

DESCRIPTION (provided by applicant): Pneumonia is a public health concern that is especially important at the 2 ends of the age spectrum. For children, pneumonia is the most common cause of death worldwide and of hospitalization in the US. Pneumonia rates plummet in early childhood and remain low for decades, until they begin rising around the fifth decade and escalate ever after. For older Americans, pneumonia confers a significantly higher risk of death compared to all other common causes of hospitalization, and half of all infectious disease hospitalizations and deaths are due to pneumonia. There is little known about the naturally acquired protection against pneumonia in most older children and young adults. We aim to elucidate this trough between the peaks of pneumonia susceptibility, to better define the immune mechanisms preventing pneumonia during late childhood and much of adulthood. We posit that heterotypic immunity, adaptive immune responses to related but not identical organisms, drives lung defense for most human-microbe interactions in the lung. For bacterial pneumonia, we propose that lung resident memory CD4+ T cells with polyfunctional Th17 phenotype are determinative, enhancing the antibacterial activities of resident alveolar macrophages and recruited neutrophils to more effectively eliminate pathogens in the deep lung. We have developed mouse models of infection-elicited heterotypic immunity against pneumococcus in the lungs, which will empower mechanistic investigations of these defenses. We will complement these studies with the first ever examinations of antibacterial responses by CD4+ T cells from human lung tissue. To test our central hypothesis that lung resident memory Th17 cells provide heterotypic immune defense against bacterial pneumonia, we will pursue 3 specific aims: (1) we will determine whether heterotypic immunity improves lung responses to bacteria via IL- 17 enhancement of phagocyte function, using mouse models of infection-elicited heterotypic protection and deletion or blockade of IL-17 signaling; (2) we will determine whether lungs contain specialized resident memory cells that drive local heterotypic antibacterial protection, using mouse models and ex vivo analyses of cells collected from fresh human lungs to investigate functional activities of resident memory CD4+ T cells; and (3) we will test whether lung heterotypic protection against pneumonia is prolonged by repeated stimulation and whether that protection declines during aging, using both mouse models and human lung patient samples. Elucidating these mechanisms protecting the lung from infection will be critical for guiding future efforts to identify subjects developing susceptibility, to counter susceptibilit, to strategize vaccine design, and to develop new therapies based on stimulating antibacterial activities from lung-resident CD4+ T cells.

描述（由申请人提供）：肺炎是一种公共卫生问题，在年龄范围的两端尤为重要。对于儿童来说，肺炎是全球最常见的死亡原因，也是美国最常见的住院原因。肺炎的发病率在幼儿期急剧下降，并在几十年内保持在低水平，直到大约50岁时才开始上升，此后不断升级。对于美国老年人来说，与所有其他常见的住院原因相比，肺炎的死亡风险显著更高，并且所有传染病住院和死亡的一半是由于肺炎。对于大多数年龄较大的儿童和年轻人对肺炎的自然获得保护知之甚少。我们的目标是阐明肺炎易感性高峰之间的低谷，以更好地定义在儿童晚期和成年大部分时间预防肺炎的免疫机制。我们认为，异型免疫，适应性免疫反应相关，但不相同的生物体，驱动肺防御大多数人-微生物在肺中的相互作用。对于细菌性肺炎，我们认为具有多功能Th 17表型的肺驻留记忆CD 4 + T细胞是决定性的，增强驻留肺泡巨噬细胞和募集的中性粒细胞的抗菌活性，以更有效地消除肺深部的病原体。我们已经建立了小鼠模型的感染引起的异型免疫对肺炎球菌在肺部，这将使这些防御机制的调查。我们将通过首次检测来自人肺组织的CD 4 + T细胞的抗菌反应来补充这些研究。为了检验我们的中心假设，即肺驻留记忆Th 17细胞提供针对细菌性肺炎的异型免疫防御，我们将追求3个具体目标：（1）我们将使用感染引起的异型保护和IL-17信号转导的缺失或阻断的小鼠模型，确定异型免疫是否通过IL-17增强吞噬细胞功能来改善肺对细菌的应答;（2）我们将确定肺是否含有驱动局部异型抗菌保护的特化驻留记忆细胞，使用小鼠模型和从新鲜人肺收集的细胞的离体分析来研究驻留记忆CD 4 + T细胞的功能活性;以及（3）我们将测试肺对肺炎的异型保护是否通过重复刺激而延长，以及这种保护是否在衰老过程中下降，使用小鼠模型和人肺患者样品。阐明这些保护肺部免受感染的机制对于指导未来的工作至关重要，以确定受试者的易感性，对抗易感性，制定疫苗设计策略，并开发基于刺激肺部驻留CD 4 + T细胞抗菌活性的新疗法。