Understanding Innate Immune Evasion as a Checkpoint for Viral Emergence

了解先天免疫逃避作为病毒出现的检查点

• 批准号: MR/X033392/1
• 负责人: Lucy Thorne
• 金额: $ 172.41万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX033392%2F1
• 关键词: Understanding; Innate; Immune; Evasion; Checkpoint

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.

在过去的二十年中，动物已经出现了许多病毒，以引起人口爆发。其中包括猪流感，埃博拉病毒，寨卡病毒和三种冠状病毒，包括SARS-COV-2，这是持续的COVID-19大流行的原因。病毒出现的频率可能是由于我们的旅行增加以及全球环境和气候变化，这会使人类和动物的接触越来越紧密。为了确定哪些病毒对未来大流行的风险构成最大的风险，重要的是要了解大流行病毒的含义，使它们能够在人类之间如此有效地传播。我们对感染的最重要的前线防御力之一是我们的先天免疫系统。该系统都存在于所有细胞中，并且由一个传感器网络组成，该网络可以检测入侵病毒，激活抗病毒防御并启动警告系统，该警告系统将相邻细胞置于停止感染的状态。要感染我们并传播，所有病毒都必须通过逃避检测或禁用反应或通常两者的复杂组合来克服这一前线防御。在冠状病毒等物种之间跳跃的病毒必须在每个新宿主中克服这种防御系统。我先前发现，尽管最近才出现在人类中，但在大流行开始时收集的SARS-COV-2分离株可以有效地抑制人类先天免疫系统的激活以允许病毒扩散。这表明该病毒是通过对抗人类防御的对策进行预防的。在整个大流行中，更可传播的变体的出现称为关注的变体（VOC），这表明SARS-COV-2正在适应其在其新人类宿主中更好地传播。我发现VOC能够比早期分离株更有效地抑制先天免疫系统的激活，这可能会增加他们建立感染传播的机会。病毒操纵可以改变先天免疫反应和驱动疾病的过程，这是由于不适当的免疫激活而损害组织的不适当，就像严重的Covid-19一样。我们的新理解共同解释了先天免疫系统如何是大流行病毒出现，传播和疾病的关键决定因素。我的研究计划的目的是了解新兴病毒如何克服先天免疫系统成为大流行。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。我首先将确定用于克服人类先天免疫防御的原始SARS-COV-2病毒的对策。这将使我发现新兴病毒的关键先天免疫障碍，并了解它们的工作原理。其次，我将调查如何适应SARS-COV-2变体，以更好地克服人类先天免疫系统以更有效地传输。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对先天免疫系统的操纵如何驱动引起疾病的不适当反应。该病毒是细胞环境的主要操纵器，使其有利于病毒复制。因此，我们可以将其用作了解先天免疫反应的出色工具，这与了解先天免疫系统有缺陷的其他疾病有关。通过这项奖学金，我将最大化我们可以从SARS-COV-2中学到的知识，为了解未来的新兴病毒奠定了基础，这些病毒都遇到了相同的防御，并发现有关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。