TLR and Notch Ligand in RSV-induced Disease

RSV 诱导疾病中的 TLR 和 Notch 配体

基本信息

批准号：
8206794
负责人：
Nicholas W Lukacs
金额：
$ 36.48万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-15 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8206794
关键词：
Address Adult Antibodies Antiviral Response Biology CD8B1 gene Cells Child Data Dendritic Cells Dendritic cell activation Development Disease Double-Stranded RNA Environment Event Generations Genes Hospitalization Immune Immune Cell Activation Immune response Immune system Immunity Individual Infant Intention Interleukin-12 Intracellular Space Knockout Mice Ligands Lung Mature T-Lymphocyte Mediating Molecular Nature Pathogenicity Pathologic Pathway interactions Pattern Pattern recognition receptor Population Production Pulmonary Pathology RNA Reagent Regulation Research Research Personnel Respiratory Syncytial Virus Infections Respiratory Tract Infections Respiratory physiology Respiratory syncytial virus Role Severities Signal Transduction System T cell differentiation T cell response T-Cell Activation T-Lymphocyte TLR3 gene TLR4 gene TLR7 gene Techniques Toll-like receptors Up-Regulation Viral Virus Virus Diseases chemokine cytokine interleukin-12 subunit p40 neutralizing antibody notch protein novel pathogen receptor research study respiratory response

项目摘要

Respiratory viral infections in infants can have devastating effects acutely on airway function, but may also impact the longterm function of the lung in both children and adults. The most common respiratory infection that is the predominant cause of hospitalization in children (>90%) is respiratory syncytial virus (RSV) infection. The initiation of the proper anti-viral responses are mandatory for successfully clearing this pathogen with minimal pathophysiologic responses. In the present proposal we will focus on the earliest immune responses to RSV infection involving the initial activation of toll- like receptors (TLRs) on dendritic cells (DCs) followed by the upregulation of important instructive signals that initiate the acquired immune responses. Recent findings have identified that notch/notch ligand induced activation has a profound role on the activation and differentiation of mature T cells. The upregulation of specific notch ligands on DCs is MyD88-dependent and provides a critical step in mature T cell differentiation. However, little is known about the role of Notch/notch ligand activation pathways for the generation of effective immune responses during virus infections. Our hypothesis for this proprosal is that TLR-mediated notch ligand delta-like 4 is required for the initiation of the appropriate immune response, and without it RSV infection becomes more pathogenic and results in an altered immune environment. These studies will specifically address several novel mechanistic questions by progressing through 3 specific aims that will 1) determine the critical TLR-induced DC activation pathway during RSV infection for anti-viral instructive signals; 2) identify the role of delta- like 4 in the development of RSV-induced immune responses and pulmonary pathology; 3) determine the differential role of plasmacytoid versus conventional DC populations for the expression of delta-like 4 and T cell activation in RSV infection. Together these individual specific aims, which are independent of one another yet clearly integrated, will each address our overall hypothesis. We will investigate these observations mechanistically using a combination of studies in gene knockout mice, specific neutralizing antibodies, and cell transfer experiments along with DC and T lymphocyte isolation. The use of specific novel reagents and advanced techniques will allow our highly integrated group of investigators to specifically target these mechanisms in a logical translational manner.

婴儿呼吸道病毒感染会对呼吸道产生严重的破坏性影响功能，但也可能影响儿童和儿童的肺的长期功能成年人。最常见的呼吸道感染，是导致该病的主要原因住院儿童（>90%）是呼吸道合胞病毒（RSV）感染。这为了成功清除这一问题，必须启动适当的抗病毒反应具有最小病理生理反应的病原体。在本提案中，我们将重点关注对RSV感染的最早免疫反应涉及toll-的初始激活树突状细胞（DC）上的样受体（TLR）随后上调重要的启动获得性免疫反应的指导信号。最近的研究结果有发现缺口/缺口配体诱导的激活对激活具有深远的作用和成熟T细胞的分化。 DC上特定Notch配体的上调是 MyD88 依赖性的，并提供成熟 T 细胞分化的关键步骤。然而，人们对Notch/Notch配体激活途径的作用知之甚少。在病毒感染期间产生有效的免疫反应。我们的假设该提议是 TLR 介导的缺口配体 delta-like 4 是启动适当的免疫反应，如果没有它，RSV 感染变得更具致病性并导致免疫环境改变。这些研究将通过进展具体解决几个新的机制问题通过 3 个具体目标，1) 确定 TLR 诱导的 DC 激活的关键 RSV感染期间抗病毒指导信号的途径； 2) 确定 delta 的作用 Like 4 在 RSV 诱导的免疫反应和肺部病理学发展中的作用； 3) 确定类浆细胞与传统 DC 群体的差异作用 RSV 感染中 Delta-like 4 的表达和 T 细胞激活。一起这些各个具体目标相互独立但又明确地结合在一起，每个都解决了我们的总体假设。我们将调查这些观察结果机械地使用基因敲除小鼠的研究组合，具体中和抗体，以及 DC 和 T 淋巴细胞的细胞转移实验隔离。使用特定的新型试剂和先进技术将使我们能够高度整合的研究人员小组专门针对这些机制逻辑翻译方式。