TLR and Notch Ligand in RSV-induced Disease

RSV 诱导疾病中的 TLR 和 Notch 配体

• 批准号: 7878285
• 负责人: Nicholas W Lukacs
• 金额: $ 1.79万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-14 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878285
• 关键词: Address; Adult; Antibodies; Antiviral Response; Biology; CD8B1 gene; Cell Differentiation process; 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 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

DESCRIPTION (provided by applicant): 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 is 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.Our studies will investigate a set of PAMP molecules known as toll-like receptors (TLRs) and their cell signaling mechanisms related to the production of cytokines, chemokines, and notch ligands. Understanding these important signaling mechanisms will allow the assessment of alterations during disease related to a lack of RSV clearance.

描述（由申请人提供）：婴儿呼吸道病毒感染会对气道功能产生严重的破坏性影响，但也可能影响儿童和成人肺的长期功能。最常见的呼吸道感染是呼吸道合胞病毒 (RSV) 感染，也是儿童 (>90%) 住院的主要原因。为了以最小的病理生理反应成功清除这种病原体，必须启动适当的抗病毒反应。在本提案中，我们将重点关注对 RSV 感染的最早免疫反应，涉及树突状细胞 (DC) 上 Toll 样受体 (TLR) 的初始激活，随后上调启动获得性免疫反应的重要指导信号。最近的研究发现，Notch/Notch 配体诱导的激活对成熟 T 细胞的激活和分化具有深远的作用。 DC 上特定缺口配体的上调依赖于 MyD88，并为成熟 T 细胞分化提供了关键步骤。然而，人们对Notch/Notch配体激活途径在病毒感染期间产生有效免疫反应的作用知之甚少。我们对此提议的假设是，TLR 介导的缺口配体 δ 样 4 是启动适当免疫反应所必需的，没有它，RSV 感染就会变得更具致病性，并导致免疫环境改变。这些研究将通过 3 个具体目标来具体解决几个新的机制问题，这些目标将 1) 确定 RSV 感染期间关键的 TLR 诱导的 DC 激活途径，以获取抗病毒指导信号； 2) 确定 delta-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 群体在 RSV 感染中 δ 样 4 表达和 T 细胞激活方面的差异作用。这些相互独立但又清晰整合的具体目标将共同解决我们的总体假设。我们将结合基因敲除小鼠的研究、特异性中和抗体、细胞转移实验以及 DC 和 T 淋巴细胞分离，从机制上研究这些观察结果。使用特定的新型试剂和先进技术将使我们高度整合的研究小组能够以逻辑翻译方式专门针对这些机制。我们的研究将研究一组称为 Toll 样受体 (TLR) 的 PAMP 分子及其与细胞因子、趋化因子和 notch 配体的产生相关的细胞信号传导机制。了解这些重要的信号传导机制将有助于评估疾病期间与缺乏 RSV 清除相关的变化。