Tollip inhibits IL-33 signaling during airway influenza virus infection

Tollip 在气道流感病毒感染期间抑制 IL-33 信号传导

基本信息

批准号：
10261956
负责人：
Hong W Chu
金额：
$ 33.26万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10261956
关键词：
Alleles Allergens Antiviral Therapy Asthma Attenuated Binding Biological Response Modifiers Body Weight decreased CRISPR/Cas technology Cell model Cells Cellular Structures Cleaved cell Confocal Microscopy Distal Dot Immunoblotting Environmental Risk Factor Epithelial Cells Exposure to Genetic Genetic Transcription Goals Goblet Cells Human Inflammation Inflammatory Influenza A virus Interleukin-13 Knockout Mice Lung MUC5AC gene Mediating Membrane Messenger RNA Mucins Mucous body substance Mus Natural Immunity Neutrophil Infiltration Pathogenesis Production Proteins Pyroglyphidae Regulation Respiratory syncytial virus Rhinovirus Role STAT3 gene Signal Transduction TOLLIP gene Testing Tissues Transcriptional Regulation Transforming Growth Factor Beta 2 Transforming Growth Factor beta Viral Viral Load result Viral Respiratory Tract Infection Virus Virus Diseases Western Blotting Work airway epithelium airway inflammation airway obstruction asthma exacerbation asthmatic asthmatic airway cytokine eosinophil epithelial injury epithelial wound influenza infection influenzavirus injured airway innovation mouse model neutrophil novel promoter receptor receptor binding respiratory infection virus respiratory virus single-cell RNA sequencing tissue injury transcription factor wound healing

项目摘要

The goal of Project 2 is to determine how Tollip protects airways from viral infection and IL-33 signaling during asthma exacerbations. Asthma exacerbations associated with respiratory infection of viruses (e.g., influenza virus) remain a significant challenge due to lack of effective antiviral therapy. These viruses primarily infect human airway epithelium. The mechanisms underlying viral infection, tissue injury and inflammation have not been well understood. In this project, we will focus on the role of a multifunctional immune regulator Toll- interacting protein (Tollip) in viral infection, particularly influenza A virus (IAV) as it represents a more severe form of viral infection in asthma. One of the key cytokines involved in asthma pathogenesis is IL-33, which is expressed by airway epithelial cells and other structural cells, and can be released during tissue injury following viral infection. Through binding to membrane-bound receptor ST2L, IL-33 exerts a variety of functions involved in asthma pathogenesis. By using a Tollip knockout mouse model of IAV infection, we discovered that Tollip deficiency increased lung viral load, loss of body weight, airway neutrophilic inflammation and importantly the release of cleaved IL-33 into the airway lumen. Mechanistically, Tollip deficiency delayed airway epithelial wound healing, reduced the production of IL-33 decoy receptor soluble ST2 (sST2), and increased mucous goblet cells expressing ST2L in IL-13-stimulated airway epithelial cells. We hereby hypothesize that Tollip is protective against viral exacerbations of asthma by inhibiting the IL-33 signaling. In Aim 1, we will define the role of Tollip in IL-33 release and activation during viral infection in airways with type 2 inflammation by testing if Tollip is protective against airway epithelial injury by promoting epithelial wound healing and reducing ATP release during respiratory viral infection in human airway epithelial cells and mouse models with type 2 inflammation. In Aim 2, we will determine sST2 regulation by Tollip during viral infection in airways with type 2 inflammation by testing if Tollip increases transcriptional activity of the ST2 proximal promoter to induce sST2 expression in part through inhibiting activation of STAT3. In Aim 3, we will determine ST2L regulation by Tollip during viral infection in airways with type 2 inflammation by testing if Tollip inhibits ST2L expression by reducing mucous goblet cells in airway epithelial cells exposed to IL-13/IL-33 and IAV. The proposed studies in Project 2 will reveal novel mechanisms by which Tollip deficiency due to genetic and/or environmental factors promotes airway injury and inflammation in a type 2 inflammation setting. sST2 or agents to reduce released ATP function/activity may serve as a therapy to correct the detrimental effect of Tollip deficiency-mediated IL-33 signaling in airways during viral exacerbations of asthma.

项目 2 的目标是确定 Tollip 如何保护气道免受病毒感染和 IL-33 信号传导哮喘恶化。与呼吸道病毒感染（例如流感病毒）相关的哮喘加重由于缺乏有效的抗病毒治疗，病毒）仍然是一个重大挑战。这些病毒主要感染人类气道上皮。病毒感染、组织损伤和炎症的机制尚未明确得到了很好的理解。在这个项目中，我们将重点关注多功能免疫调节剂 Toll- 的作用。病毒感染中的相互作用蛋白（Tollip），特别是甲型流感病毒（IAV），因为它代表了更严重的哮喘病毒感染的一种形式。 IL-33是参与哮喘发病机制的关键细胞因子之一由气道上皮细胞和其他结构细胞表达，并且可以在组织损伤后释放病毒感染。通过与膜结合受体 ST2L 结合，IL-33 发挥多种相关功能在哮喘发病机制中。通过使用 IAV 感染的 Tollip 基因敲除小鼠模型，我们发现 Tollip 缺乏会增加肺部病毒载量、体重减轻、气道中性粒细胞炎症，重要的是将裂解的 IL-33 释放到气道腔中。从机制上讲，Tollip 缺乏会延迟气道上皮伤口愈合，减少 IL-33 诱饵受体可溶性 ST2 (sST2) 的产生，并增加粘液杯状细胞在 IL-13 刺激的气道上皮细胞中表达 ST2L。我们特此假设 Tollip 具有保护作用通过抑制 IL-33 信号传导来对抗哮喘的病毒性恶化。在目标 1 中，我们将定义以下角色：通过测试 Tollip 是否会影响 2 型炎症气道病毒感染期间 Tollip 的 IL-33 释放和激活通过促进上皮伤口愈合和减少 ATP 释放来防止气道上皮损伤在人呼吸道上皮细胞和患有 2 型炎症的小鼠模型中进行呼吸道病毒感染期间。在目标 2，我们将确定 Tollip 在 2 型炎症气道病毒感染期间对 sST2 的调节测试 Tollip 是否增加 ST2 近端启动子的转录活性以部分诱导 sST2 表达通过抑制 STAT3 的激活。在目标 3 中，我们将确定病毒感染期间 Tollip 的 ST2L 调节通过测试 Tollip 是否通过减少粘液杯状细胞抑制 ST2L 表达来治疗患有 2 型炎症的气道暴露于 IL-13/IL-33 和 IAV 的气道上皮细胞中。项目 2 中拟议的研究将揭示新颖的遗传和/或环境因素导致的 Tollip 缺乏促进气道损伤的机制 2 型炎症环境中的炎症。 sST2 或减少释放的 ATP 功能/活性的药物可能起作用作为一种治疗方法，可纠正病毒感染期间气道中 Tollip 缺陷介导的 IL-33 信号传导的不利影响哮喘恶化。