Understanding Innate Immune Evasion as a Checkpoint for Viral Emergence

在过去的二十年里，从动物身上出现了许多病毒，在人类中引起了疫情。这些病毒包括猪流感、埃博拉病毒、寨卡病毒和三种冠状病毒，其中包括导致当前COVID-19大流行的SARS-CoV-2。病毒出现的频率正在加快，可能是由于我们旅行的增加以及全球环境和气候变化使人类和动物更加密切接触。为了确定哪些病毒对未来的大流行构成最大的风险，重要的是要了解大流行病毒的特点，使它们能够在人类之间如此有效地传播。我们抵御感染最重要的一线防线之一是我们的先天免疫系统。该系统存在于所有细胞中，由一个传感器网络组成，可以检测入侵病毒，激活抗病毒防御，并启动一个警告系统，使邻近细胞处于停止感染的准备状态。为了感染和传播我们，所有病毒都必须克服这道防线，要么逃过检测，要么使反应失效，或者通常是两者的复杂结合。在物种之间跳跃的病毒，如冠状病毒，必须在每个新宿主中克服这种防御系统。我之前发现，尽管最近才在人类中出现，但在大流行开始时收集的SARS-CoV-2分离株可以有效抑制人类先天免疫系统的激活，从而允许病毒传播。这表明该病毒预先配备了对抗措施，以克服人类的防御。在整个大流行期间，出现了更具传染性的变体，称为关注变体（VOCs），这表明SARS-CoV-2正在适应在其新的人类宿主中更好地传播。我发现挥发性有机化合物能够比早期分离的更有效地抑制先天免疫系统的激活，这可能会增加它们建立感染传播的机会。操纵病毒可以改变先天免疫反应的进程，引发疾病，导致免疫激活不当，损害组织，严重的COVID-19就会发生这种情况。总之，我们的新认识有助于解释先天免疫系统如何在大流行病毒的出现、传播和疾病中起关键决定作用。我的研究计划的目标是了解新出现的病毒如何克服先天免疫系统而成为流行病。实时研究SARS-CoV-2及其对人类的适应性，为了解人类感染的分子机制提供了无与伦比的机会。我将首先确定最初的SARS-CoV-2病毒用来克服人类先天免疫防御的对策。这将引导我发现针对新出现病毒的关键先天免疫屏障，并了解它们是如何工作的。其次，我将研究SARS-CoV-2变体如何适应，以更好地克服人类先天免疫系统，从而更有效地传播。这将揭示先天免疫系统的哪些方面是人类独有的。第三，我将发现SARS-CoV-2如何操纵先天免疫系统驱动导致疾病的不适当反应。病毒是细胞环境的操纵者，使其有利于病毒复制。正因为如此，我们可以用它作为一个很好的工具来了解先天免疫反应是如何工作的，这与理解先天免疫系统有缺陷的其他疾病有关。通过这项奖学金，我将最大限度地从SARS-CoV-2中学到东西，为理解未来新出现的病毒奠定基础，这些病毒都会遇到同样的防御，并发现关于先天免疫系统如何在健康和疾病中起作用的令人兴奋的新生物学。

In the past two decades numerous viruses have emerged from animals to cause outbreaks in the human population. These include Swine Flu, Ebola viruses, Zika virus, and three coronaviruses, including SARS-CoV-2, the cause of the ongoing COVID-19 pandemic. The frequency of virus emergence is accelerating likely due to our increased travel as well as global environmental and climate changes that bring humans and animals in ever closer contact. To identify which viruses pose the most risk for future pandemics, it's important to understand what it is about pandemic viruses that enables them to spread so efficiently between humans. One of our most important front-line defences against infection is our innate immune system. This system is present in all cells, and is made up of a network of sensors that can detect invading viruses, activate antiviral defences and initiate a warning system that places neighbouring cells in a state of readiness to stop infection. To infect us and transmit, all viruses must overcome this front-line defence, by escaping detection or by disabling the response or usually a complex combination of both. Viruses that jump between species, such as coronaviruses, must overcome this defence system in each new host. I previously found that, despite having only recently emerged in humans, isolates of SARS-CoV-2 collected at the start of the pandemic could effectively suppress activation of the human innate immune system to allow viral spread. This suggests the virus was pre-armed with countermeasures to overcome human defences. The emergence of more transmissible variants throughout the pandemic, called variants of concern (VOCs), suggests that SARS-CoV-2 is adapting to spread better in its new human host. I discovered that the VOCs were able to suppress activation of the innate immune system even more potently than the early isolates, which may increase their chance of establishing infection to transmit. Virus manipulation can change the course of the innate immune response and drive disease, resulting from inappropriate immune activation that damages tissues, as occurs in severe COVID-19. All together our new understanding helps explain how the innate immune system is a key determinant in pandemic virus emergence, transmission, and disease.The goal of my research programme is to understand how emerging viruses overcome the innate immune system to become pandemic. Studying SARS-CoV-2, and its adaptation to humans in real time, provides an unparalleled opportunity to understand the molecular mechanisms underlying human infection. I will firstly identify the countermeasures the original SARS-CoV-2 virus used to overcome human innate immune defences. This will lead me to discover key innate immune barriers to emerging viruses and understand how they work. Secondly, I will investigate how SARS-CoV-2 variants have adapted to get better at overcoming the human innate immune system to transmit more effectively. This will reveal what aspects of the innate immune system are unique to humans. Thirdly, I will discover how SARS-CoV-2 manipulation of the innate immune system drives inappropriate responses that cause disease. The virus is a master manipulator of the cell environment to make it conducive for viral replication. Because of this, we can use it as an excellent tool to learn how the innate immune response works, which is relevant to understanding other diseases where the innate immune system is defective. Through this fellowship, I will maximise what we can learn from SARS-CoV-2 to lay the groundwork for understanding future emerging viruses, which all encounter the same defences, and discover exciting new biology about how the innate immune system works in health and disease.