Mechanisms of Airway Epithelial Barrier Dysfunction by Respiratory Syncytial Virus and Environmental Stimuli

呼吸道合胞病毒和环境刺激导致气道上皮屏障功能障碍的机制

基本信息

批准号：
10657436
负责人：
Fariba Rezaee
金额：
$ 43.99万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657436
关键词：
3-Dimensional Actin-Binding Protein Actins Acute Adult Adverse effects Affect Age Air Pollution Airway Disease Antioxidants Apical Artificial nanoparticles Attenuated Cell Separation Child Childhood Complex Cyclic AMP Cytoskeleton Data Deposition Distal Down-Regulation EMS1 gene Environmental Pollutants Environmental Pollution Epidemiology Epithelial Cells Epithelium Event Exposure to Filament Free Radicals Functional disorder Generations Hospitalization Host Defense Household Human Human Cell Line In Vitro Infant Inflammation Injury Knockout Mice Link Lower Respiratory Tract Infection Lung Measurement Mediating Methods Microfilaments Mission Modeling Molecular Monomeric GTP-Binding Proteins Morbidity - disease rate Mus Nanotechnology Organoids Outcome Oxidative Stress Oxidative Stress Induction Particle Size Particulate Matter Pathology Pathway interactions Personal Satisfaction Polymers Production Reporting Research Respiration Disorders Respiratory Syncytial Virus Infections Respiratory syncytial virus Risk Rodent Role Severities Signaling Molecule Source Standardization Stimulus Structure Testing Therapeutic Intervention United States National Institutes of Health Vascular Endothelium Vascular Permeabilities Virus Virus Diseases Virus Replication airway epithelium airway hyperresponsiveness bronchial epithelium clinically relevant commercial application consumer product depolymerization design epithelial injury gain of function high risk in vivo in vivo Model injured airway innovation insight intestinal epithelium loss of function mortality mouse model nanomaterials nanoparticle new therapeutic target novel particle polymerization titanium dioxide young adult

项目摘要

ABSTRACT Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections (ALRI) in children and high-risk adults worldwide. Our data demonstrate that RSV infection results in a ‘leaky airway’ by disrupting epithelial apical junctional complexes (AJC), which regulate the airway epithelial barrier. We show that RSV- mediated disruption of AJC is accompanied by disassembly of the perijunctional actin cytoskeleton, and downregulation of cortactin - a key actin-binding protein. Cortactin deficiency has been previously implicated in destabilizing the vascular endothelial and intestinal epithelial barrier. However the causal link between RSV- induced leaky barrier, actin cytoskeletal rearrangements and cortactin deficiency have not been established. In addition, epidemiological reports suggest a strong association between exposure to ambient particulate matter (PM) and increased risk of ALRI. Nanoparticles (NPs) are extremely small PM, with the greater ability to become deposited in distal airways and evade host defenses compared to smaller particles. Our preliminary data demonstrate that pre-exposure of bronchial epithelial cells to NP not only enhances RSV-induced AJC disassembly and actin cytoskeleton disruption, but augments viral infection. Based on our novel observations, we formulated the central hypotheses that a) RSV induces disruption of the airway epithelial barrier by triggering depolymerization of the perijunctional actin cytoskeleton, and by downregulating cortactin; and b) that disruption of the epithelial barrier by nanoparticles worsens RSV-induced airway epithelium injury. We will test our hypotheses through the following Specific Aims: Aim 1: To determine the role of cortactin-dependent actin filament dynamics in RSV-induced airway epithelial barrier dysfunction. Using human bronchial epithelial cells isolated from pediatric donors, and a mouse model of cortactin null mice, we will investigate (i) RSV effect on actin cytoskeletal dynamics, (ii) the functional role of cortactin on actin dynamics and AJC structure, and (iii) the functional roles of Rap-1. We will also use a 3-D human lung organoids model detailing the effects of AJC disruption upon RSV infection, which offers an innovative platform to study complex host-environmental interactions. Aim 2: To determine if nanoparticles enhance RSV-induced disruption of the airway epithelial barrier. Using in vitro and in vivo models, we will (i) characterize the effects of particle size on barrier integrity, (ii) study role of oxidative stress on AJC function, and (iii) define the effects of exposure to NP on AJC dysfunction. The proposed research is significant and relevant to the NIH’s mission as we aim to explore the clinically relevant consequences of RSV infection on airway barrier integrity, and how exposure to environmental pollutants worsens RSV infection. Our approach is innovative because it will provide new mechanistic insight in to the roles of RSV in AJC disassembly, as well as novel insight in to the effects of NPs in enhancing RSV- induced AJC disruption. The identified pathways will provide new targets for therapeutic intervention and the potential for positively impacting the management of RSV disease.

抽象的呼吸道合胞病毒（RSV）是儿童急性下呼吸道感染（ALRI）的主要原因我们的数据表明，RSV 感染会扰乱呼吸道，导致“气道漏气”。上皮顶端连接复合物（AJC），它调节气道上皮屏障，我们发现RSV-。 AJC 介导的破坏伴随着连接周围肌动蛋白细胞骨架的分解，并且 Cortactin 的下调（一种关键的肌动蛋白结合蛋白）先前已被认为与 Cortactin 缺乏有关。然而，RSV- 之间的因果关系破坏了血管内皮和肠上皮屏障的稳定性。诱导的渗漏屏障、肌动蛋白细胞骨架重排和皮质蛋白缺乏尚未确定。此外，流行病学报告表明，暴露于环境颗粒物之间存在很强的关联性。 (PM) 和 ALRI 风险增加纳米颗粒 (NP) 是极小的 PM，具有更大的变成能力。与较小的颗粒相比，它们沉积在远端气道并逃避宿主防御。证明支气管上皮细胞预先暴露于 NP 不仅可以增强 RSV 诱导的 AJC 分解和肌动蛋白细胞骨架破坏，但会增加病毒感染，根据我们的新观察，我们提出了中心假设：a) RSV 通过触发来诱导气道上皮屏障的破坏 b) 通过下调皮质蛋白来解聚连接周围肌动蛋白细胞骨架；纳米颗粒对上皮屏障的破坏会加剧 RSV 诱导的气道上皮损伤。通过以下具体目标提出假设：目标 1：确定皮质蛋白依赖性肌动蛋白的作用使用人支气管上皮细胞研究 RSV 诱导的气道上皮屏障功能障碍的细丝动力学。从儿科捐赠者和皮质素缺失小鼠模型中分离出来，我们将研究 (i) RSV 对肌动蛋白细胞骨架动力学，(ii) cortactin 对肌动蛋白动力学和 AJC 结构的功能作用，以及 (iii) 我们还将使用 3D 人类肺类器官模型来详细说明 AJC 的作用。 RSV 感染的破坏，为研究复杂的宿主环境提供了一个创新平台目标 2：确定纳米粒子是否增强 RSV 诱导的气道上皮破坏。使用体外和体内模型，我们将 (i) 表征粒径对屏障完整性的影响， (ii) 研究氧化应激对 AJC 功能的作用，以及 (iii) 定义暴露于 NP 对 AJC 的影响拟议的研究具有重要意义，并且与 NIH 的使命相关，因为我们的目标是探索功能障碍。 RSV 感染对气道屏障完整性的临床相关后果，以及暴露于环境的方式我们的方法是创新的，因为它将提供新的机制见解。 RSV 在 AJC 分解中的作用，以及对 NP 在增强 RSV 中的作用的新见解所确定的途径将为治疗干预和治疗提供新的目标。对 RSV 疾病的管理产生积极影响的潜力。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Vitamin D3 protects against respiratory syncytial virus-induced barrier dysfunction in airway epithelial cells via PKA signaling pathway.

维生素 D3 通过 PKA 信号通路防止呼吸道合胞病毒引起的气道上皮细胞屏障功能障碍。

DOI：
发表时间：
2023-09
期刊：
影响因子：
6.6
作者：
Gao, Nannan;Raduka, Andjela;Rezaee, Fariba
通讯作者：
Rezaee, Fariba

Effects of Vertical Transmission of Respiratory Viruses to the Offspring.

呼吸道病毒垂直传播对后代的影响。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Manti, Sara;Leonardi, Salvatore;Rezaee, Fariba;Harford, Terri J;Perez, Miriam K;Piedimonte, Giovanni
通讯作者：
Piedimonte, Giovanni

Respiratory syncytial virus disrupts the airway epithelial barrier by decreasing cortactin and destabilizing F-actin.

呼吸道合胞病毒通过减少皮质蛋白和破坏 F-肌动蛋白的稳定性来破坏气道上皮屏障。

DOI：
发表时间：
2022-08-15
期刊：
影响因子：
4
作者：
Gao, Nannan;Raduka, Andjela;Rezaee, Fariba
通讯作者：
Rezaee, Fariba

The importance of anti-vaping vigilance-EVALI in seven adolescent pediatric patients in Northeast Ohio.

俄亥俄州东北部七名青少年儿科患者反电子烟警惕性的重要性 - EVALI。

DOI：
发表时间：
2020
期刊：
影响因子：
3.1
作者：
Corcoran, Aoife;Carl, John C;Rezaee, Fariba
通讯作者：
Rezaee, Fariba

Role of air pollutants in airway epithelial barrier dysfunction in asthma and COPD.

空气污染物在哮喘和慢性阻塞性肺病气道上皮屏障功能障碍中的作用。

DOI：
发表时间：
2022-03-31
期刊：
影响因子：
0
作者：
Aghapour, Mahyar;Ubags, Niki D;Bruder, Dunja;Hiemstra, Pieter S;Sidhaye, Venkataramana;Rezaee, Fariba;Heijink, Irene H
通讯作者：
Heijink, Irene H