Project 2: Innate Immunity

项目2：先天免疫

• 批准号: 10674303
• 负责人: BALI PULENDRAN
• 金额: $ 186.57万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-02 至 2023-06-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10674303
• 关键词: ATAC-seq; Acute; Adaptive Immune System; Address; Adjuvant; Antibody Response; Antigens; Attenuated; B-Lymphocytes; Blood; CD14 gene; COVID-19; Cells; Complement; Cytometry; Data; Dendritic Cells; Dendritic cell activation; Dengue Infection; Deuterium; Deuterium Oxide; Development; Epigenetic Process; Exhibits; FCGR3B gene; Frequencies; Genetic Transcription; Homeostasis; Human; Immunity; Immunologic Memory; Infection; Inflammatory; Inflammatory Response; Innate Immune System; Kinetics; Knowledge; Label; Ligands; Longevity; Mediating; Memory; Molecular; Mus; Myelogenous; Myeloid Cells; Natural Immunity; Natural Killer Cells; Paracrine Communication; Peripheral Blood Mononuclear Cell; Population; Property; Proteins; Role; Secondary Immunization; Signal Transduction; Structure of germinal center of lymph node; T memory cell; T-Lymphocyte; Testing; Time; Training; Vaccination; Work; Yellow Fever Vaccine; adaptive immune response; adaptive immunity; base; chromatin modification; imprint; in vivo; lymph nodes; monocyte; nanoparticle; nonhuman primate; novel strategies; pathogen; response; transcriptome sequencing

Immunological memory is a hallmark of antigen-specific T and B lymphocytes. In contrast, the innate immune system is known to launch rapid, non-specific effector responses, which are short-lived. However, recent studies have proposed a form of immunological memory in the innate immune system, where innate cells can “remember” a pathogen encounter for several weeks to months. This phenomenon of “trained immunity” has been documented for NK cells, but less is known about its role in monocytes and dendritic cells (DCs). Innate memory has been suggested to be mediated via epigenetic changes in myeloid cells, but there are several fundamental questions about the mechanisms of innate memory. In this proposal, we will address the following questions in the context of vaccination with the live attenuated yellow fever vaccine 17D (YFV-17D) or acute dengue viral infection in humans, and in mechanistic studies in mice: 1. Unlike memory T and B cells, most DC and monocyte subsets are believed to have a relatively short lifespan of a few days. So how can epigenetic changes acquired by such short-lived cells mediate innate memory? Can subsets of myeloid-derived cells persist for several weeks after infection or vaccination? 2. To what extent is so called “innate memory” caused by the effects of an ongoing adaptive immune response (for example, via paracrine signaling), versus a cell intrinsic property of innate cells, similar to the classic phenomenon of immune memory exhibited by memory T or B cells? 3. Is there an enhanced response of DCs and monocytes, (similar to a memory response in the adaptive immune system), during secondary vaccination or infection? If so, what are the cellular and molecular mechanisms involved? We will address these questions in the following aims: Aim 1. Determining the innate response and regulatory landscape of DCs and monocytes in response to YFV-17D vaccination and dengue infection in humans. Aim 2: To determine the turnover rates of DCs and monocytes in response to YFV-17D vaccination in humans, using heavy water labeling. Aim 3: To define the mechanisms of innate memory induced by YFV-17D and adjuvants. Successful completion of these aims will further our mechanistic understanding of the phenomenon of innate memory, and offer novel strategies inducing broad and durable protection against diverse pathogens.

免疫记忆是抗原特异性T和B淋巴细胞的标志。相反，先天免疫 已知系统会启动短暂的快速，非特异性效应子响应。但是，最近的研究 在先天免疫系统中提出了一种免疫记忆形式，先天细胞可以 “记住”病原体遇到数周到几个月。这种“受过训练的免疫”现象具有 已记录在NK细胞中，但对其在单核细胞和树突状细胞（DC）中的作用知之甚少。先天 已经建议记忆是通过髓样细胞的表观遗传变化介导的，但是有几种 关于先天记忆机制的基本问题。在此提案中，我们将解决以下内容 在疫苗的背景下进行的问题，带有活衰减的黄热疫苗17D（YFV-17D）或急性 人类的登革热病毒感染以及小鼠的机理研究： 1。与记忆T和B细胞不同，大多数DC和单核细胞子集的寿命相对较短 几天。那么，这种短寿命的细胞媒体天生记忆如何获得表观遗传变化呢？ 感染或疫苗接种后几周，髓样细胞的子集可以持续数周吗？ 2。在多大程度上所谓的“先天记忆”是由持续的适应性免疫响应的影响引起的 （例如，通过旁分泌信号传导）与先天细胞的固有特性相比，类似于经典 记忆T或B细胞暴露的免疫记忆现象？ 3。是否有增强的DC和单核细胞的响应（类似于自适应中的记忆响应 免疫系统），在继发疫苗接种或感染期间？如果是这样，细胞和分子是什么 涉及的机制？我们将在以下目的中解决这些问题： 目的1。确定DC和单核细胞的先天反应和调节景观 人类的YFV-17D疫苗接种和登革热感染。 目标2：确定DC和单核细胞的周转率，以响应于YFV-17D疫苗接种 人类，使用重水标签。 目标3：定义YFV-17D和调节器引起的先天记忆的机制。 这些目标的成功完成将进一步进一步我们对先天现象的机械理解 记忆并提供新颖的策略可引起对潜水病原体的广泛和耐用的保护。