Understanding Innate Immune Evasion as a Checkpoint for Viral Emergence

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.