Autophagy regulation of RSV-induced pulmonary disease

RSV 诱导的肺部疾病的自噬调节

基本信息

批准号：
8515518
负责人：
Nicholas W Lukacs
金额：
$ 36.46万
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：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8515518
关键词：
2 year old Adult Affect Age Alzheimer&apos s Disease Antigen Presentation Antigen-Presenting Cells Antiviral Response Area Asthma Attention Autophagocytosis Autophagosome Cell Differentiation process Cell Maturation Cell membrane Cell physiology Cells Child Chronic Chronic Obstructive Airway Disease Critical Pathways Data Deacetylase Defect Dendritic Cells Dendritic cell activation Development Digestion Disease Elderly Endosomes Environment Generations Genes Hospitalization Immune Immune response Immune system Immunocompromised Host Immunologics In Vitro Individual Infant Infection Investigation Lead Lower Respiratory Tract Infection Lung Lung diseases Lysosomes Mediating Membrane Fusion Modeling Molecular Morbidity - disease rate Mucosal Immune Responses Mucous body substance Mus Natural Immunity Organelles Parkinson Disease Pathogenesis Pathology Pathway interactions Pattern Pattern Recognition Phenotype Physiological Pneumonia Process Production Proteins Pulmonary Pathology Reaction Regulation Resources Respiratory Syncytial Virus Infections Respiratory syncytial virus Role Severities Signal Transduction Supraoptic Vertical Ophthalmoplegia System T cell response T-Cell Activation T-Cell Development Testing Therapeutic Vaccine Design Viral Virus Virus Diseases chemokine clinically relevant cytokine human disease in vivo interest normal aging novel pathogen receptor respiratory response vaccine development

项目摘要

DESCRIPTION (provided by applicant): The regulation of anti-viral immune responses in the lung is dependent upon the ability to efficiently and appropriately recognize pathogenic signals and promote the proper and non-pathogenic response to clear the viral infection. Respiratory syncytial virus (RSV) is an especially pathogenic virus that can induce morbidity at all ages, especially in infants and those with underlying lung conditions. Recent data has indicated that a critical innate immune pathway that is functional for pathogen recognition is autophagy. This omnipresent process provides all cells the ability to not only preserve resources but transport pathogen components to the proper immune recognition molecules, PAMPs. Our studies have identified that recognition of RSV infection by dendritic cells (DC) depends upon autophagy for the most appropriate, nonpathogenic response in the lungs. Thus, our overall hypothesis is that RSV infection responses depend upon autophagy to generate an effective immune response through the induction of critical innate cytokines in APC within the lungs. We will test this hypothesis using both in vitro and in vivo analyses with our RSV infection model and extend the findings to demonstrate that autophagy-mediated recognition of the viral infection dictates that direction of the acquired immune response, lending to the severity of the response. Using specific gene knockdown and genetically deficient mice, including Beclin +/- and LC3B-/- mice, we will explore how the absence of autophagy mechanisms alters anti-RSV responses in vitro and in vivo. Subsequently, we will further explore an important mechanism of initiation of the autophagy responses by examining a NAD deacetylase, sirt1, known to initiate autophagosome formation. Using our established model of RSV infection that recapituates several aspects of human disease, including mucus hypersecretion, physiologic changes (AHR) and a pathogenic cytokine profile, these investigations will be able to thoroughly characterize the mechanistic changes associated with these critical pathways. Thus, these studies will explore several novel and topical pathways that can not only further define the mechanisms that promote pulmonary mucosal immune responses, but expand our understanding of rationale vaccine design for RSV.

描述（由申请人提供）：肺部抗病毒免疫反应的调节取决于有效且适当地识别致病信号并促进适当的非致病反应以清除病毒感染的能力。呼吸道合胞病毒 (RSV) 是一种致病性特别强的病毒，可导致所有年龄段的患者发病，尤其是婴儿和患有潜在肺部疾病的患者。最近的数据表明，对病原体识别起作用的关键先天免疫途径是自噬。这种无所不在的过程使所有细胞不仅能够保存资源，还能将病原体成分转运到适当的免疫识别分子 PAMP 上。我们的研究发现，树突状细胞 (DC) 对 RSV 感染的识别取决于自噬，以在肺部产生最适当的非致病性反应。因此，我们的总体假设是，RSV 感染反应依赖于自噬，通过诱导肺内 APC 中关键的先天细胞因子来产生有效的免疫反应。我们将使用 RSV 感染模型进行体外和体内分析来测试这一假设，并扩展研究结果以证明自噬介导的病毒感染识别决定了获得性免疫反应的方向，从而决定了反应的严重程度。使用特定基因敲低和遗传缺陷小鼠，包括 Beclin +/- 和 LC3B-/- 小鼠，我们将探索自噬机制的缺失如何改变体外和体内的抗 RSV 反应。随后，我们将通过检查已知可启动自噬体形成的 NAD 脱乙酰酶 Sirt1，进一步探索启动自噬反应的重要机制。使用我们建立的 RSV 感染模型来概括人类疾病的几个方面，包括粘液分泌过多、生理变化 (AHR) 和致病性细胞因子谱，这些研究将能够彻底表征与这些关键途径相关的机制变化。因此，这些研究将探索几种新颖的局部途径，这些途径不仅可以进一步定义促进肺粘膜免疫反应的机制，而且可以扩大我们对 RSV 疫苗设计原理的理解。