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

• 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
• 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

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信号转导， 哮喘恶化。与呼吸道病毒感染相关的哮喘恶化（例如，流感 病毒）由于缺乏有效的抗病毒治疗仍然是一个重大挑战。这些病毒主要感染 人气道上皮细胞病毒感染、组织损伤和炎症的潜在机制尚未阐明。 被很好地理解。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， 相互作用蛋白（Tollip）在病毒感染中的作用，特别是甲型流感病毒（IAV），因为它代表了一种更严重的 哮喘中的病毒感染形式。参与哮喘发病机制的关键细胞因子之一是IL-33，其是 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期间释放， 病毒感染通过与膜结合受体ST 2L结合，IL-33发挥多种功能，包括 在哮喘发病机制中的作用。通过使用Tollip基因敲除的IAV感染小鼠模型，我们发现Tollip 缺乏增加肺病毒载量，体重减轻，气道嗜酸性炎症，重要的是， 裂解的IL-33释放到气道腔中。从机制上讲，Tollip缺乏症延迟气道上皮损伤 愈合，减少IL-33诱饵受体可溶性ST 2（sST 2）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ST 2L。我们在此假设托利普是在保护 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 Tollip在2型炎症气道病毒感染期间IL-33释放和活化中的作用， 通过促进上皮伤口愈合和减少ATP释放来保护气道上皮免受损伤 在人气道上皮细胞和2型炎症小鼠模型中呼吸道病毒感染期间。在 目的2，我们将通过以下方法确定Tollip在2型炎症气道病毒感染期间对sST 2的调节： 测试Tollip是否增加ST 2近端启动子的转录活性以部分诱导sST 2表达 通过抑制STAT 3的激活。在目标3中，我们将确定Tollip在病毒感染期间对ST 2L的调节 通过测试Tollip是否通过减少粘液杯状细胞来抑制ST 2L表达， 在暴露于IL-13/IL-33和IAV的气道上皮细胞中。项目2中的拟议研究将揭示新的 由遗传和/或环境因素引起的Tollip缺陷促进气道损伤的机制， 在2型炎症环境中的炎症。sST 2或降低释放的ATP功能/活性的试剂可用于 作为一种治疗方法，以纠正Tollip缺陷介导的IL-33信号传导在病毒感染期间的气道中的有害作用， 哮喘恶化。