Cellular and molecular programming of lung resident T cell memory

肺驻留 T 细胞记忆的细胞和分子编程

• 批准号: 10115800
• 负责人: JACOB E KOHLMEIER
• 金额: $ 77.53万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10115800
• 关键词: Animal Model; Antibody Response; Automobile Driving; Biology; Cells; Cessation of life; Development; Epigenetic Process; Event; Future; Generations; Genetic Transcription; Goals; Health; Hemagglutinin; Human; Humoral Immunities; Immunity; Infection; Influenza; Influenza vaccination; Knowledge; Longevity; Lung; Maintenance; Mediating; Medical Care Costs; Molecular; Mus; Positioning Attribute; Proteins; Sampling; Site; Structure of parenchyma of lung; Symptoms; T memory cell; Testing; Time; Tissues; Vaccination; Vaccine Design; Viral; Viral Load result; biobank; design; improved; influenza infection; influenzavirus; novel; pathogen; programs; respiratory pathogen; response; seasonal influenza; transmission process; vaccination strategy; vaccine development; vaccinology

PROJECT SUMMARY Influenza virus is a major health burden worldwide, resulting in billions of dollars in medical costs and up to 600,00 deaths annually. Thus, a major challenge of pulmonary vaccinology is to develop an approach that will provide long-lasting and durable immunity in the lung. Seasonal influenza infection is driven largely by antigenic shift to avoid established antibody responses, limiting the efficacy of current influenza vaccinations designed to generate humoral immunity to the hemagglutinin protein. One approach to this problem is the development of vaccines designed to promote the generation of influenza-specific, lung-resident T cell memory. In animal models and human studies, memory T cells have been shown to significantly reduce viral loads after influenza challenge, leading to faster viral clearance, decreased transmission, and milder or sub- clinical symptoms. Lung tissue-resident memory T cells (lung TRM) have been found to be critical for this protective cellular response to influenza, but lung TRM numbers gradually decline over time. Despite thie importance for pulmonary immunity, we still have only a basic understanding of the cellular and molecular mechanisms that control their generation and long-term maintenance, nor have we identified the optimal vaccination strategies to induce durable lung TRM. Furthermore, the influence on unique microenvironments of the lung interstitium and lung airways on TRM biology is poorly understood. This proposal seeks to develop a program in lung TRM biology centered on three related themes: (i) investigating the molecular programming of TRM that enables their generation following infection and vaccination; (ii) defining the cell- and tissue-intrinsic mechanisms that drive the gradual loss of lung TRM and testing the ability of novel vaccinations strategies to improve lung TRM longevity; and (iii) determining the transcriptional and epigenetic programming of influenza- specific lung TRM at the bulk and single cell level using a biorepository of human lung samples. The overall goal of this project is to understand the mechanisms driving the initial generation and subsequent decline of influenza-specific TRM from the lung interstitium and airways. The knowledge gained in this study will provide a deep understanding of the mechanisms that regulate lung TRM biology to better inform future vaccine design against respiratory pathogens.

项目摘要 流感病毒是全球主要的健康负担，导致了数十亿美元的医疗费用 每年600,00人死亡。因此，肺疫苗学的主要挑战是开发一种方法 在肺部提供持久耐用的免疫力。季节性流感感染主要由 抗原转移以避免已建立的抗体反应，从而限制了当前流感疫苗接种的功效 旨在产生对血凝素蛋白的体液免疫。解决这个问题的一种方法是 开发旨在促进流感特异性肺居民T细胞产生的疫苗 记忆。在动物模型和人类研究中，记忆T细胞已被证明可显着降低病毒 流感挑战后的负载，导致病毒清除率更快，传播降低以及温和或亚下 临床症状。肺组织居住记忆T细胞（肺TRM）对此至关重要 保护性细胞对流感的反应，但随着时间的流逝，肺TRM数量逐渐下降。尽管盗贼 对于肺免疫的重要性，我们仍然只有对细胞和分子的基本了解 控制其产生和长期维护的机制，我们也没有确定最佳 诱导耐用肺TRM的疫苗接种策略。此外，对独特微环境的影响 TRM生物学上的肺间质和肺气道知之甚少。该建议旨在发展 肺TRM生物学的程序以三个相关主题为中心：（i）研究分子编程 在感染和疫苗接种后能够使其一代的TRM； （ii）定义细胞和组织内膜 驱动肺TRM逐渐丧失并测试新型疫苗接种策略的能力的机制 改善肺部TRM寿命； （iii）确定流感的转录和表观遗传编程 使用人类肺样品的生物库，在散装和单细胞水平的特定肺TRM。总体目标 这个项目的是了解推动初始一代的机制，随后下降 来自肺间质和气道的流感特异性TRM。这项研究中获得的知识将提供 对调节肺TRM生物学的机制有深刻的了解，以更好地告知未来的疫苗设计 针对呼吸道病原体。