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（由申请方提供）：婴儿呼吸道病毒感染可对气道功能产生急性破坏性影响，但也可能影响儿童和成人的长期肺功能。最常见的呼吸道感染是儿童住院的主要原因（>90%），是呼吸道合胞病毒（RSV）感染。启动适当的抗病毒反应是成功清除这种病原体的必要条件，同时具有最小的病理生理反应。在本发明中，我们将集中于对RSV感染的最早免疫应答，其涉及树突细胞（DC）上toll样受体（TLR）的初始活化，随后是启动获得性免疫应答的重要指导性信号的上调。最近的研究发现，notch/notch配体诱导的活化对成熟T细胞的活化和分化具有深远的作用。DC上特异性notch配体的上调是MyD 88依赖性的，并且提供了成熟T细胞分化的关键步骤。然而，关于Notch/Notch配体激活途径在病毒感染期间产生有效免疫应答的作用知之甚少。我们对这种proproprosal的假设是TLR介导的notch配体δ样4是启动适当免疫应答所需的，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3个具体目标的进展来具体解决几个新的机制问题，所述3个具体目标将1）确定RSV感染期间用于抗病毒指导信号的关键TLR诱导的DC活化途径; 2）鉴定δ样4在RSV诱导的免疫应答和肺病理学的发展中的作用; 3）确定浆细胞样与常规DC群体对于RSV感染中δ样4表达和T细胞活化的不同作用。这些各自的具体目标相互独立，但又清晰地整合在一起，将分别解决我们的总体假设。我们将使用基因敲除小鼠、特异性中和抗体和细胞转移实验沿着DC和T淋巴细胞分离的研究组合来机械地研究这些观察结果。使用特定的新试剂和先进的技术将使我们高度整合的研究人员团队能够以逻辑翻译的方式专门针对这些机制。我们的研究将研究一组被称为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允许评估疾病期间与缺乏RSV清除相关的改变。