Innate immune programming of humoral immunity to flaviviruses

对黄病毒的体液免疫的先天免疫编程

基本信息

批准号：
9067905
负责人：
Edward A Clark
金额：
$ 37.46万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9067905
关键词：
Adaptor Signaling Protein Affinity Antibodies Antibody Response Antigens Antiviral Response Attenuated B-Cell Development B-Lymphocytes Binding CD19 gene CD4 Positive T Lymphocytes Cell Lineage Cells Characteristics Collaborations Data Defect Dendritic Cells Dengue Virus Development Diphtheria Toxin Elements Event Family member Flavivirus Genes Goals Humoral Immunities IFNAR1 gene ITGAX gene Immune Immune response Immunity Immunoglobulin G Immunoglobulin M Infection Inflammatory Interferon Type I Interferons Japanese Encephalitis Knockout Mice Lead Life Madagascar Mature B-Lymphocyte Memory B-Lymphocyte Mitochondria Mus Myeloid Cells Pathway interactions Plasma Cells Play Predisposition Production Program Development Regimen Reporter Resources Role Signal Transduction Splenic Red Pulp Structure of germinal center of lymph node T cell response Testing Vaccines Viral Viral Antibodies Viral Pathogenesis Virus Virus Diseases West Nile viral infection West Nile virus Work Yellow Fever adaptive immunity base cell type cytokine diphtheria toxin receptor insight macrophage monocyte mouse model neuropathology neutralizing antibody novel strategies novel vaccines programs receptor recombinase-mediated cassette exchange response sensor stem type I interferon receptor vaccine response viral RNA

项目摘要

Although neutralizing antibodies (NAbs) are essential for protection after infection of many flaviviruses, relatively little is known about the key early events in innate immune cells that lead to effective neutralizing Ab responses. RIG-I like receptor (RLR) family members sense viral RNA and through the mitochondria associated adaptor protein MAVS, induce antiviral responses including the production of type I interferons (IFNs). Both MAVS and type I IFN pathways regulate Ab responses to viruses. In Project 3 we will determine the specific cell types that require MAVS and the type I IFN receptor (IFNAR) signaling to help develop the rapid first line Ab defense to WNV and later germinal center-dependent high affinity and long-lived NAb and memory B cell responses. Using a set of conditional knockout mice with either MAVS or IFNAR deleted in a cell type restricted manner, we will determine how MAVS or IFNAR function in dendritic cells (DCs), macrophages or B cells help develop effective humoral immunity to West Nile virus (WNV), an encephalitic flavivirus featured in this U19 program. As BAFF, a type I IFN-inducible cytokine, is essential for normal B cell development and responses to antigens, we also will define the role ofthe BAFF receptors, BAFFR and BCMA in humoral immune responses to WNV and determine which cells must produce BAFF for long-lived immunity to develop. Finally, as both monocytes and macrophages play important roles in both innate and adaptive responses to flaviviruses, we define how and when these cells contribute to flavivirus humoral immunity using mouse models in which subsets of these cells are deleted. Overall, this work will provide new insights in the interface between the innate immune and humoral responses, which may facilitate novel strategies for creating optimal humoral vaccine responses against flaviviruses.

尽管中和抗体 (NAb) 对于许多黄病毒感染后的保护至关重要，但我们对先天免疫细胞中导致有效中和抗体反应的关键早期事件知之甚少。 RIG-I 样受体 (RLR) 家族成员感知病毒 RNA 并通过线粒体相关接头蛋白 MAVS 诱导抗病毒反应，包括产生 I 型干扰素 (IFN)。 MAVS 和 I 型 IFN 通路均调节抗体对病毒的反应。在项目 3 中，我们将确定需要 MAVS 和 I 型干扰素受体 (IFNAR) 信号传导的特定细胞类型，以帮助开发针对 WNV 的快速一线抗体防御，以及随后的生发中心依赖性高亲和力和长寿命 NAb 和记忆 B细胞反应。使用一组以细胞类型限制方式删除 MAVS 或 IFNAR 的条件性基因敲除小鼠，我们将确定 MAVS 或 IFNAR 在树突状细胞 (DC)、巨噬细胞或 B 细胞中如何发挥作用，帮助开发针对西尼罗河病毒 (WNV) 的有效体液免疫。），这是该 U19 计划中的一种脑炎黄病毒。由于 BAFF（一种 I 型 IFN 诱导细胞因子）对于正常 B 细胞发育和对抗原的反应至关重要，因此我们还将定义 BAFF 受体、BAFFR 和 BCMA 在针对 WNV 的体液免疫反应中的作用，并确定哪些细胞必须产生 BAFF长期免疫力得以发展。最后，由于单核细胞和巨噬细胞在对黄病毒的先天性和适应性反应中都发挥着重要作用，因此我们使用删除了这些细胞子集的小鼠模型来定义这些细胞如何以及何时促进黄病毒体液免疫。总体而言，这项工作将为先天免疫和体液反应之间的界面提供新的见解，这可能有助于制定针对黄病毒的最佳体液疫苗反应的新策略。