Innate interferons in epithelial defence against respiratory viruses

呼吸道病毒是对人类健康和经济繁荣的主要威胁。例子包括流感和导致冠状病毒病19(新冠肺炎)的病毒，SARS-CoV-2。为了开发抗击这些病毒的医学干预措施，我们需要更好地了解靶细胞对病毒感染的正常免疫反应，例如排列在呼吸道-肺部呼吸道的细胞。通过对异常严重的新冠肺炎患者的仔细研究，似乎某些免疫因素在呼吸道感染的最早阶段起到了限制疾病的重要作用。这些因素被称为‘干扰素’。干扰素是由病毒感染的细胞产生的。它们向未感染病毒的邻居发出信号，要求他们采取“抗病毒状态”来阻止病毒传播。两种主要类型的干扰素是由呼吸道细胞产生的，I型和III型干扰素。因此，病毒进化出几种策略来逃避这种反应。I型和III型干扰素是不同的因素，但具有相似的作用机制。然而，人们对它们的单独功能或它们如何在人体内相互作用知之甚少。了解这一点将告诉我们如何最好地操纵个体干扰素类型以获得临床益处。我们对人类患者的研究告诉了我们宝贵的教训。携带I型干扰素系统突变的患者容易患严重的新冠肺炎，这表明I型干扰素在预防病毒感染的严重后果方面发挥着至关重要的作用。有趣的是，这些人正常应对大多数其他呼吸道病毒，如流感，就像那些有III型干扰素系统特定损害的人一样。然而，I型和III型干扰素系统受损的患者可能会因为许多呼吸道病毒而发展成严重的疾病。基于这些观察，我提出I型和III型干扰素在保护呼吸道方面相互弥补，但在某些情况下，存在缺口，可被SARS-CoV-2等病毒利用。我将使用新的尖端实验室模型。我们利用的干细胞在理论上能够转化为人体内任何其他类型的细胞。我们已经开发出一种方法，将它们转化为排列在呼吸道内的细胞。我们将它们暴露在空气中，与呼吸道中发生的情况相匹配。然后我们用不同的病毒感染呼吸道细胞，包括导致新冠肺炎的SARS-CoV-2和流感。我们将测量病毒的生长情况以及它们对呼吸道细胞造成的损害。使用干细胞创造这些呼吸道细胞的原因是，我们可以在干细胞的DNA中引入“拼写错误”，阻止它们对干扰素产生反应。通过比较病毒在这些不同呼吸道细胞中的行为，我们将了解哪些干扰素在控制特定病毒方面是重要的。我们还将使用测量单个细胞反应的技术来测量对这些病毒的免疫反应。这将帮助我们确定干扰素的工作方式，并允许我们进行更详细的实验来证实我们的发现。我们还将调查特殊免疫细胞对这一过程的影响，这些细胞通常存在于呼吸道中。我们认为它们将有助于呼吸道细胞的干扰素反应。最后，我们将在病毒感染的啮齿动物模型中进行实验，以评估这些干扰素如何在完好的有机体的呼吸道中发挥作用。同时，这些结果将解释这些免疫因子是如何工作的，并深入了解这些明显独立的系统的目的。这可能是宿主故意采取的策略，以减轻病毒逃避干扰素的影响，也可能是它们协同工作，或者单独更好地对抗某些病毒。这一信息与干扰素用于治疗或预防病毒性疾病的临床使用有关。

Respiratory viruses are a major threat to human health and economic prosperity. Examples include influenza and the virus that causes coronavirus disease 19 (COVID-19), SARS-CoV-2. In order to develop medical interventions to combat these viruses, we need to better understand the normal immune response to viral infection in target cells, such as the cells that line the airways - the air passages of the lung. Through the careful study of patients with unusually severe COVID-19, it appears that certain immune factors play an important role in limiting disease at the earliest stages of infection in the airway.These factors are known as 'interferons'. Interferons are produced by virally infected cells. They signal uninfected neighbours to adopt an 'antiviral state' that blocks viral spread. Two major types of interferons are made by airway cells, type I and type III interferons. Consequently, viruses have evolved several strategies to evade this response.Type I and III interferons are distinct factors but share similar mechanisms of action. However, little is known about their individual functions or how they interact in humans. Understanding this will tell us how best to manipulate individual interferon types for clinical benefit. Our study of human patients with rare 'spelling errors' in their DNA (mutations) that affect the interferon pathways teach us valuable lessons.Patients with mutations of the type I interferon system are vulnerable to severe COVID-19, suggesting that type I interferons play an essential role in protecting against serious consequences of viral infection. Interestingly, these individuals cope normally with most other respiratory viruses, such as influenza, as do those with specific lesions of the type III interferon system. However, patients with impairment of both type I and III interferon systems can develop severe disease due to many respiratory viruses. Based on these observations, I propose that type I and III interferons compensate for one another in the defence of the airway, but that in some cases there are gaps that viruses such as SARS-CoV-2 exploit.I will use new cutting-edge laboratory models. We make use of stem cells that, in theory, are able to turn into any other type cell type in the human body. We have developed a way to turn them into cells that line the airway. We expose them to air, matching what happens in the airway. We then infect airway cells with different viruses, including SARS-CoV-2 - which causes COVID-19 - and influenza. We will measure the growth of the viruses and the damage that they cause to the airway cells. The reason for using stem cells to create these airway cells is that we can introduce 'spelling errors' into the DNA of the stem cell, preventing them from responding to interferons. By comparing the behaviour of the virus in these different airway cells, we will learn which interferons are important in controlling specific viruses.We will also measure the immune response to these viruses using techniques to measure the responses of individual cells. This will help us to identify the way that interferons work and allow us to do more detailed experiments to confirm our findings. We will also investigate the impact of specialised immune cells, present normally in the airway, on this process. We think that they will aid the interferon response of airway cells. Finally, we will conduct experiments in a rodent model of viral infection to assess how these interferons operate in the airway in the intact organism.Together, these results will explain how these immune factors work and give insight into the purpose of these apparently independent systems. It is possible that this is a deliberate strategy by the host to mitigate against viral evasion of interferons, or it may be that they work together, or are individually better against certain viruses. This information is relevant to the clinical use of interferons to treat or prevent viral disease.