Autophagy regulation of RSV-induced pulmonary disease

RSV 诱导的肺部疾病的自噬调节

• 批准号: 8687732
• 负责人: Nicholas W Lukacs
• 金额: $ 37.51万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/8687732
• 关键词: 2 year old; Adult; Affect; Age; Alzheimer' 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

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）：肺中抗病毒免疫应答的调节取决于有效和适当识别致病信号并促进适当和非致病应答以清除病毒感染的能力。呼吸道合胞病毒（RSV）是一种特别致病的病毒，可在所有年龄段引起发病，特别是在婴儿和患有潜在肺部疾病的人中。最近的数据表明，对病原体识别起作用的一个关键先天免疫途径是自噬。这种无所不在的过程为所有细胞提供了不仅保护资源，而且将病原体成分运输到适当的免疫识别分子PAMP的能力。我们的研究已经确定，树突状细胞（DC）对RSV感染的识别依赖于自噬，以获得肺中最合适的非致病性反应。因此，我们的总体假设是RSV感染应答依赖于自噬，通过诱导肺内APC中的关键先天性细胞因子来产生有效的免疫应答。我们将使用RSV感染模型的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应答的方向，从而导致应答的严重程度。使用特定基因敲除和遗传缺陷小鼠，包括Beclin +/-和LC 3B-/-小鼠，我们将探索自噬机制的缺乏如何改变体外和体内的抗RSV反应。随后，我们将进一步探索启动自噬反应的重要机制，通过检查NAD脱乙酰酶，sirt 1，已知启动自噬体形成。使用我们建立的RSV感染模型，重现了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的和局部的途径，不仅可以进一步确定促进肺粘膜免疫应答的机制，而且可以扩大我们对RSV疫苗设计原理的理解。