Innate interferons in epithelial defence against respiratory viruses

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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.