Innate Immunity and Viral Infection in Asthma

哮喘的先天免疫和病毒感染

基本信息

批准号：
10661638
负责人：
Monica Kraft
金额：
$ 143.16万
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/10661638
关键词：
2019-nCoV ACE2 Acceleration Airway Disease Allergens Allergic Disease Alveolar Asthma Attenuated Bronchoscopy Chronic Clinical Collaborations Communication Data Disease Distal Epithelial Cells Event Exhibits Genetic Transcription Genotype Homeostasis Human IL6 Signaling Pathway Immune Immune response Immunity Immunologic Factors Immunomodulators In Vitro Infection Infectious Agent Inflammation Inflammatory Influenza Influenza A virus Innate Immune Response Interleukin-13 Irritants Lung diseases Mediating Mediator Modeling Molecular Mus Natural Immunity Nose Participant Pathway interactions Phase Phenotype Phosphatidylglycerols Phosphatidylinositols Phospholipids Physiological Positioning Attribute Production Productivity Pulmonary Surfactant-Associated Protein A Pyroglyphidae Research Resources Respiratory System Rhinovirus Risk Factors Role SARS-CoV-2 infection Sampling Severities Shipping Signal Transduction Supplementation TOLLIP gene Testing Tissues Viral Virus Virus Diseases Work asthma exacerbation atopy bronchial epithelium clinically relevant cytokine data management innate immune function innovation novel novel strategies novel therapeutics programs protective effect receptor receptor binding recruit response surfactant synergism tool

项目摘要

In this AADCRC program renewal, we will focus on three critical and understudied innate immune factors and how they impact viral infections in asthma: the anionic phospholipids of surfactant (palmitoyl- oleoyl-phosphatidylglycerol, POPG, and phosphatidylinositol, PI), Toll interacting protein (Tollip), and surfactant protein-A (SP-A). Because these mediators have complementary functions to modulate inflammation and immunity in asthma and infection, we propose three interrelated, synergistic, self-standing projects to investigate how these mediators orchestrate novel innate immune responses associated with viral infections in asthma. We will study three viruses with a spectrum of effects in airway disease, and determine how innate responses protect against them. Specifically, we will focus on rhinovirus C (RV-C), a known exacerbator of asthma that can cause severe disease; influenza A, a virus whose effect in asthma remains ambiguous and SARS-CoV-2, a virus that can cause severe lung disease, but for which asthma may not be a risk factor, and may in fact confer protection. We show innovative preliminary data indicating that 1) POPG, PI and SP-A attenuate RV-C infection; 2) Tollip exhibits protective effects as it is required for IL-13 to generate soluble ST2 that in turn attenuates the effects of IL-33 during influenza A infection; and 3) SP-A and type 2 cytokines confer protection in the effector and initiation phases of SARS-CoV-2 infection in asthma by inhibiting the expression and function of ACE2, the SARS-CoV-2 receptor, through effects upon transcription, receptor binding and downstream pro-inflammatory signaling. Thus, all these innate immune components appear to protect against viral infections in asthma. Our exciting preliminary data underpin our program’s overall hypothesis that POPG/PI, Tollip and SP-A function as unique immune modulators that attenuate the impact of specific viral infections (RV-C, Influenza A and SARS-CoV-2) in type-2 asthma. Therefore, supplementation of functional POPG/PI, SP-A and the IL-33 decoy receptor sST2 may be novel strategies against asthma exacerbations due to viral infections. Project 1 will critically test the activity of POPG/PI and SP- A supplementation as a novel molecular tool for disrupting infections due to RV-C, a virus known to exacerbate asthma. Project 2 will determine how Tollip protects against viral exacerbations caused by influenza A in asthma through inhibition of IL-33 signaling. Project 3 will determine how type-2 cytokines and SP-A synergize to protect against SARS-CoV-2 infection through inhibition of ACE2-mediated infection and IL-6 signaling pathways. We also include an Administrative Core and a Clinical Core, both which serve all projects equally. We build upon productive collaborations of over 20 years on innate molecular mechanisms underlying the interaction between type 2 inflammation and viral exacerbations of asthma. The strong synergy among our three projects will accelerate progress toward novel therapies by demonstrating that the innate immune components under study protect against viral infection in asthma.

在此AADCRC计划续签中，我们将重点关注三个关键和知识的先天免疫因素以及它们如何影响哮喘病毒感染：表面活性剂的阴离子磷脂（棕榈酰 - 烯烃 - 磷脂酰甘油，POPG和磷脂酰肌醇，PI），TOLL相互作用蛋白（TOLLIP）和表面活性剂蛋白A（SP-A）。因为这些调解人具有完整的功能来调节哮喘和感染中的炎症和免疫力，我们提出了三个相互关联的，协同的，自我的项目旨在调查这些介体如何协调与病毒相关的新型先天免疫反应哮喘感染。我们将研究三种在气道疾病中具有各种作用的病毒，以及确定天生的反应如何保护它们。具体而言，我们将重点关注Rhinovirus C（RV-C），A 可能导致严重疾病的哮喘的已知恶化；影响力的病毒，其在哮喘中的作用仍然存在模棱两可和SARS-COV-2，一种可能引起严重肺部疾病的病毒，但哮喘可能不是风险因素，实际上可能会提供保护。我们显示创新的初步数据，表明1）POPG，PI SP-A减弱RV-C感染； 2）Tollip表现出受保护的效果，因为IL-13需要生成可溶性的ST2反过来减轻了影响力感染期间IL-33的影响； 3）SP-A和类型2 通过抑制SARS-COV-2感染的效应子和主动性阶段的细胞因子会议保护通过抑制通过对转录，受体的影响ACE2，SARS-COV-2受体ACE2的表达和功能结合和下游促炎信号传导。那就是所有这些先天的免疫组件似乎预防哮喘中的病毒感染。我们令人兴奋的初步数据支撑了我们计划的整体数据 popg/pi，tollip和sp-a起独特的免疫调节剂的假设，特定病毒感染（RV-C，流感和SARS-COV-2）在2型哮喘中的影响。所以，功能性POPG/PI，SP-A和IL-33诱饵受体SST2的补充可能是新型策略因病毒感染而导致的哮喘恶化。项目1将对POPG/PI和SP-的活性进行严格的测试补充是一种新型分子工具，用于破坏因RV-C而引起的感染，RV-C是一种已知病毒的病毒哮喘。项目2将确定Tollip如何预防哮喘影响力引起的病毒加剧通过抑制IL-33信号传导。项目3将决定2型细胞因子和SP-A协同作用以保护通过抑制ACE2介导的感染和IL-6信号通路来抵抗SARS-COV-2感染。我们还包括行政核心和临床核心，两者都同等地服务于所有项目。我们基于在20多年的生产性合作上，在固有分子机制上的相互作用的固有机制 2型哮喘的炎症和病毒加重。我们三个项目之间的强大协同作用将通过证明先天免疫成分下的新疗法的进步加速了新疗法研究预防哮喘中的病毒感染。