Role of Tollip in dysfunction of asthma airway innate immunity

Tollip 在哮喘气道先天免疫功能障碍中的作用

• 批准号: 9156370
• 负责人: Hong W Chu
• 金额: $ 39.93万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9156370
• 关键词: Allergens; Antiviral Response; Asthma; Autophagocytosis; Bacterial Infections; Biological Response Modifiers; Bronchoalveolar Lavage Fluid; Cell Culture Techniques; Data; Defense Mechanisms; Distal; Epithelial; Epithelial Cells; Functional disorder; Genes; Genetic Variation; Genotype; Goals; Heterogeneity; Host Defense; Human; IL8 gene; IRAK1 gene; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferons; Interleukin-13; Invaded; Knockout Mice; Lung; Lung Inflammation; Lung diseases; Measures; Mus; Natural Immunity; Nose; Pathway interactions; Production; Proteins; Pulmonary Surfactant-Associated Protein A; Pyroglyphidae; Receptor Signaling; Respiratory physiology; Rhinovirus; Role; Severities; Severity of illness; Single Nucleotide Polymorphism; TOLLIP gene; Testing; Toll-like receptors; Transgenic Mice; Viral; Virus Diseases; abstracting; airway hyperresponsiveness; airway inflammation; asthmatic; cell type; cytokine; eosinophil; genetic variant; improved; mouse model; neutrophil; pathogen; personalized management; prevent; programs; protein expression; respiratory; response; surfactant

Project Summary/Abstract: The goal of this project is to determine the role of Toll-interacting protein (Tollip) in regulating lung defense against rhinovirus infection related to asthma exacerbations. Tollip has been proposed as a negative immune regulator for host defense against bacterial infections. It is widely expressed by various types of cells, including lung epithelial cells. Tollip single nucleotide polymorphisms (SNPs) have been identified, but the role of Tollip in asthma has not been investigated. We found that Tollip rs5743899 AG genotype is more frequent in asthmatics than normal controls. Importantly, asthmatics with the AG genotype demonstrate lower lung function than asthmatics with the AA genotype. Moreover, human airway epithelial cells carrying the AG genotype express less Tollip than the AA genotype. The combination of type 2 cytokine IL-13 and rhinovirus further decreases Tollip expression. Epithelial cells carrying the AG genotype demonstrate, when treated with IL-13 and rhinovirus (RV), a stronger pro-inflammatory response, but weaker anti-viral response. We therefore hypothesize that reduction of Tollip in a subset of genetically defined asthmatics, especially in the setting of type 2 inflammation and viral infection, exaggerates airway inflammation and asthma severity. Aim 1 will determine the role of Tollip rs5743899 in asthma lung inflammation, infection and function. By using brushed human bronchial and nasal epithelial cells and bronchoalveolar lavage fluid from asthmatics and normal subjects, we will measure Tollip expression, inflammatory and anti-viral responses, and rhinovirus burden. These data along with the surfactant protein A2 (SP-A2) genetic variant data will then be correlated with asthma lung function and disease severity. Aim 2 will determine mechanisms by which Tollip regulates inflammation and viral infection in asthma. By using primary human bronchial and nasal epithelial cell cultures, and Tollip and autophagy gene knockout mouse models of allergen exposure and rhinovirus infection, we will test the hypothesis that in a type 2 cytokine milieu, Tollip inhibits the Toll-like receptor (TLR) signaling and pro-inflammatory cytokine production, but enhances the anti-viral response via enhancing the autophagy activity. Aim 3 will determine cooperation of Tollip and SP-A in airway defense against viral infections. By using SP-A and Tollip knockout and transgenic mouse models of allergen exposure and rhinovirus infection, we will test the hypothesis that Tollip cooperates with SP-A to inhibit airway viral infections in asthma. SP-A maintains or increases Tollip levels, which in turn further decreases airway inflammation and viral infection. Successful completion of Project 2 will deepen our understanding of airway innate immunity dysfunction in asthma. The role of Tollip in asthma is not known and may act in concert with SP-A to further modulate response to RV during asthma exacerbations. Unraveling Tollip genetic variation and function may improve our understanding of asthma heterogeneity and corresponding personalized disease management.

项目摘要/摘要： 该项目的目的是确定Toll-Interacting蛋白（Tollip）在调节肺防御中的作用 针对与哮喘加重有关的鼻病毒感染。 Tollip已被认为是负免疫 宿主防御细菌感染的调节剂。它被各种类型的细胞广泛表达，包括 肺上皮细胞。 Tollip单核苷酸多态性（SNP）已被鉴定出来，但是Tollip的作用 尚未研究哮喘。我们发现Tollip RS5743899 Ag基因型在 哮喘患者比正常对照。重要的是，具有AG基因型的哮喘患者表现出较低的肺 功能比AA基因型的哮喘患者。此外，人类气道上皮细胞携带Ag 基因型表达的Tollip少于AA基因型。 2型细胞因子IL-13和鼻病毒的组合 进一步降低了Tollip的表达。当用Ag基因型的上皮细胞与 IL-13和鼻病毒（RV），一种更强的促炎反应，但抗病毒反应较弱。因此，我们 假设在遗传定义的哮喘患者子集中减少Tollip，尤其是在 2型炎症和病毒感染的设置，夸大气道炎症和哮喘 严重程度。 AIM 1将确定Tollip RS5743899在哮喘肺部炎症，感染和功能中的作用。通过使用 哮喘患者和 正常受试者，我们将测量Tollip表达，炎症和抗病毒反应以及鼻病毒病毒 负担。这些数据以及表面活性剂蛋白A2（SP-A2）遗传变异数据将相关 哮喘功能和疾病严重程度。 AIM 2将确定Tollip调节哮喘中炎症和病毒感染的机制。经过 使用原发性人支气管和鼻皮细胞培养物，以及Tollip和自噬基因敲除 过敏原暴露和鼻病毒感染的小鼠模型，我们将测试以下假设。 Tollip细胞因子环境抑制了类似收费的受体（TLR）信号传导和促炎性细胞因子的产生， 但通过增强自噬活性来增强抗病毒反应。 AIM 3将确定Tollip和SPA在气道防御病毒感染中的合作。通过使用sp-a 以及过敏原暴露和鼻病毒感染的Tollip敲除和转基因小鼠模型，我们将测试 Tollip与SP-A合作以抑制哮喘中气道病毒感染的假设。 SP-A保持或 提高了Tollip水平，从而进一步降低了气道炎症和病毒感染。 成功完成项目2将加深我们对气道先天免疫功能障碍的理解 哮喘。 Tollip在哮喘中的作用尚不清楚，并且可以与SP-A一起起作用以进一步调节 哮喘加重期间对RV的反应。解开托利普的遗传变异和功能可能会改善我们的 了解哮喘异质性和相应的个性化疾病管理。