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

摘要 2019年冠状病毒病（COVID-19）的持续爆发，由严重急性 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。 鼻道是呼吸道病毒感染的主要入口， 这表明鼻上皮是SARS-CoV-2的关键储存库，也是病毒的来源。 这种脱落导致了COVID-19的高传染性和高发病率。我们 假设在受感染的鼻粘膜中干扰素诱导的先天性免疫应答减弱， 上皮细胞是允许病毒快速复制而无细胞毒性的主要机制。的 父母补助金的重点是人类鼻窦上皮细胞群如何参与免疫 防御和损伤修复。在本补充提案中，为了响应NOT-AI-20-031，我们 将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.具体地说，延迟的干扰素信号传导可以防止一氧化氮的诱导， 其先前已显示抑制病毒进入和复制。氧化氮可以 在鼻上皮中由干扰素以外的刺激物诱导，包括通过激活苦味 在纤毛上表达的味觉感受器。临床上有许多批准的药物 使用苦味并能与苦味受体结合。其中，某些抗恶心 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SARS-CoV-2感染原代鼻上皮细胞的能力 体外然后，我们将使用苦味信号和一氧化氮的药理学调节剂， 建立减少感染的药物作用机制的途径。我们还将 确定这些药物是否影响干扰素对SARS-CoV-2感染的反应。如果 成功的，这些研究可能为新的治疗方法奠定基础，以提高 最初的上皮细胞天然免疫防御SARS-CoV-2感染，限制 COVID-19的进展和传染性的下降。

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.