Innate Immune Regulation of the Epithelium in Chronic Rhinosinusitis with Nasal Polyps

慢性鼻窦炎伴鼻息肉上皮的先天免疫调节

基本信息

批准号：
10187233
负责人：
ANDREW P LANE
金额：
$ 14.14万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-16 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10187233
关键词：
2019-nCoV Agonist Antiemetics Antihistamines Antimalarials Antiviral Agents Binding COVID-19 Cells Cilia Clinical Diphenhydramine Disease Outbreaks Double-Stranded RNA Emergency Situation Environment Epithelial Epithelial Cells Epithelium Foundations Generations Genes Goals Hour Human Immune Immune response In Vitro Individual Infection Inflammatory Inflammatory Response Innate Immune Response Interferon-beta Interferons Kinetics Membrane Mucous body substance NOS2A gene Nasal Epithelium Nasal Polyps Nasal cavity Nausea Nitric Oxide Nitric Oxide Pathway Nitric Oxide Synthase Nitric Oxide Synthetase Inhibitor Nose Peptide Hydrolases Pharmaceutical Preparations Pharmacology Phospholipase C Play Population Predisposition Primary Infection Production Protein Kinase Receptor Signaling Research Respiratory Tract Infections Role SARS coronavirus Signal Pathway Signal Transduction Signaling Molecule Sinus Source Stimulus Taste Buds Taste Perception Testing Tissues Upper respiratory tract Viral Viral Load result Viral Respiratory Tract Infection Virus Virus Diseases Virus Replication Virus Shedding Work airway epithelium chronic rhinosinusitis cytokine cytotoxicity drug action global health immunoregulation improved inhibitor/antagonist novel therapeutic intervention pandemic disease parent grant pathogenic virus prevent receptor repaired response transmission process

项目摘要

ABSTRACT The ongoing outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a major threat to global health. The nasal passages are the key portal of entry for airway virus infections, and evidence suggests that the nasal epithelium is a key reservoir for SARS-CoV-2 and a source of viral shedding that accounts for high transmissibility and elevated rates of COVID-19. We hypothesize that diminished interferon-induced innate immune responses in infected nasal epithelial cells is a primary mechanism allowing rapid viral replication without cytotoxicity. The parent grant focuses on how human sinonasal epithelial cell populations participate in immune defense and damage repair. In this supplement proposal, in response to NOT-AI-20-031, we will extend these studies to research in depth the epithelial cell innate immune response to SARS-CoV-2. Specifically, delayed interferon signaling may prevent induction of nitric oxide, which has been previously shown to inhibit viral entry and replication. Nitric oxide can be induced in nasal epithelial by stimuli other than interferon, including through activation of bitter taste receptors expressed on the cilia. There are a number of approved medications in clinical use that taste bitter and can bind to bitter taste receptors. Among these, certain anti-nausea and antihistamines are particularly strong bitter taste agonists. In this proposal, we will test the ability of these medications to inhibit SARS-CoV-2 infection of primary nasal epithelial cells in vitro. We will then use pharmacologic modulators of the bitter taste signaling and nitric oxide pathways to establish the mechanism of action of drugs that decrease infection. We will also determine if these medications impact the interferon response to SARS-CoV-2 infection. If successful, these studies may lay the foundation for novel therapeutic approaches to enhance the initial epithelial cell innate immune defense against SARS-CoV-2 infection, limiting progression of COVID-19 and decreasing transmissibility.

抽象的 2019 年冠状病毒病 (COVID-19) 的持续爆发，由严重急性流感引起呼吸综合征冠状病毒2（SARS-CoV-2）已成为全球健康的主要威胁。鼻道是气道病毒感染的关键入口，证据表明鼻上皮是 SARS-CoV-2 的关键储存库和病毒来源脱落导致了 COVID-19 的高传播性和高发病率。我们假设减少了受感染鼻腔中干扰素诱导的先天免疫反应上皮细胞是允许病毒快速复制而无细胞毒性的主要机制。这家长资助重点关注人类鼻腔上皮细胞群如何参与免疫防御和损伤修复。在此补充提案中，为了回应 NOT-AI-20-031，我们将把这些研究扩展到深入研究上皮细胞的先天免疫反应 SARS-CoV-2。具体来说，延迟的干扰素信号传导可能会阻止一氧化氮的诱导，此前已被证明可以抑制病毒进入和复制。一氧化氮可以由干扰素以外的刺激（包括通过激活苦味）在鼻上皮中诱导味觉感受器在纤毛上表达。目前已有多种药物获得临床批准使用味道苦并且可以与苦味受体结合的物质。其中，某些抗恶心药抗组胺药是特别强的苦味激动剂。在本提案中，我们将测试这些药物抑制原代鼻上皮细胞 SARS-CoV-2 感染的能力体外。然后我们将使用苦味信号传导和一氧化氮的药理调节剂建立减少感染药物作用机制的途径。我们也会确定这些药物是否影响干扰素对 SARS-CoV-2 感染的反应。如果如果成功的话，这些研究可能会为新的治疗方法奠定基础，以增强上皮细胞针对 SARS-CoV-2 感染的初始先天免疫防御，限制了 COVID-19 的进展和传播性的降低。