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，而先天免疫则相反。 众所周知，该系统会启动快速、非特异性的效应器反应，但这种反应是短暂的。 提出了先天免疫系统中的一种免疫记忆形式，先天细胞可以 这种“训练有素的免疫力”的现象已经“记住”了病原体的遭遇数周至数月。 NK 细胞已被记录，但对其在单核细胞和先天树突状细胞 (DC) 中的作用知之甚少。 记忆被认为是通过骨髓细胞的表观遗传变化介导的，但有几种 在本提案中，我们将解决以下有关先天记忆机制的基本问题。 有关接种黄热病减毒活疫苗 17D (YFV-17D) 或急性黄热病疫苗的问题 人类登革热病毒感染以及小鼠的机制研究： 1. 与记忆T细胞和B细胞不同，大多数DC和单核细胞亚群被认为寿命相对较短 那么，这种短命细胞获得的表观遗传变化如何调节先天记忆呢？ 骨髓源性细胞亚群在感染或接种疫苗后能否持续存在数周？ 2.所谓的“先天记忆”在多大程度上是由持续的适应性免疫反应的影响引起的 （例如，通过旁分泌信号传导），与先天细胞的细胞内在特性相比，类似于经典的 免疫记忆现象是由记忆T细胞还是B细胞表现出来的？ 3. DC和单核细胞的反应是否增强（类似于适应性记忆反应） 免疫系统），在二次疫苗接种或感染期间，如果是这样，细胞和分子是什么？ 我们将通过以下目标解决这些问题： 目标 1. 确定 DC 和单核细胞响应的先天反应和调节环境 YFV-17D 疫苗接种和人类登革热感染。 目标 2：确定 DC 和单核细胞响应 YFV-17D 疫苗接种的周转率 人类，使用重水标签。 目标 3：确定 YFV-17D 和佐剂诱导先天记忆的机制。 成功完成这些目标将进一步加深我们对先天现象的机械理解。 记忆，并提供新颖的策略，诱导广泛而持久的保护，抵御多种病原体。