A review published in the BSI's journal Clinical & Experimental Immunology summarises current knowledge of the innate immune response following SARS‐CoV‐2 infection and how it may contribute to damage of the blood vessels in severe COVID-19 cases.
SARS-CoV-2, the virus that causes the disease COVID-19, belongs to the Coronaviridae family of viruses. Much of our knowledge about the way the immune system responds to SARS-CoV-2 infection is based on studies of other coronaviruses, particularly SARS-CoV – the virus responsible for the 2002 SARS outbreak.
SARS-CoV-2 initially escapes innate immunity
SARS-CoV-2 gains entry to human cells through a receptor known as angiotensin-converting enzyme 2 (ACE2). ACE2 is found on the surface of cells that line the lungs, heart, blood vessels, kidneys, intestinal tract and testes, as well as other cells. Binding of the SARS-CoV-2 virus to ACE2 receptors activates inflammation and is likely the first step in a series of damaging immune responses.
Innate immunity refers to nonspecific responses of the immune system to e.g. pathogens (viruses and bacteria) that can be rapidly activated following infection. Like many viruses, SARS‐CoV‐2 has evolved strategies to evade innate immune detection, such as masking viral RNA (genetic material) and generating viral proteins that actively block anti‐viral responses. As a result, widespread viral replication can continue unchecked, leading to a massive ‘viral load’ – the amount of virus that the infected person is producing.
Overstimulation of innate immunity is implicated in severe COVID-19
After evading the innate immune system in early SARS-CoV-2 infection, rapid production of viral RNA and viral proteins then triggers a harmful excessive innate immune response. Infected cells are damaged and burst, releasing new virus particles and damaged cell fragments that trigger further inflammatory responses.
Studies of blood and post-mortem tissue from severe COVID-19 cases reveal high levels of signalling molecules and specialised immune cells involved in the inflammasome – a pathway that leads to a highly inflammatory form of cell death called pyroptosis.
While respiratory damage and complications are one of the major clinical signs of severe COVID-19, damage to the blood vessels and widespread blood clotting are also emerging as key pathological features. Accordingly, post-mortem tissues from COVID-19 cases show signs of strong activation of the complement system – another arm of the innate immune pathway which enhances the ability of specialised immune cells to engulf and kill virus-infected cells. Infection also leads to the recruitment of innate immune cells called neutrophils, which contribute to blood clotting as well as triggering tissue damage.
Controlling severe COVID-19
Overstimulation of innate immunity is a key factor that can affect disease severity following SARS-CoV-2 infection. Further studies are needed to examine whether risk factors such as advanced age, obesity and cancer contribute to severe COVID-19 through their effects on innate immune components.
Identifying the innate immune factors that are overstimulated following SARS-CoV-2 infection and understanding how these contribute to respiratory and blood vessel damage will be crucial for managing severe cases. Many studies are now exploring whether therapies used for other viral infections or inflammatory diseases can be repurposed to target abnormal innate immune responses in COVID-19 patients.
Amor, S., Blanco, L. F. and Baker, D. (2020) Innate immunity during SARS‐CoV‐2: evasion strategies and activation trigger hypoxia and vascular damage. Clinical & Experimental Immunology. doi: 10.1111/cei.13523
Paper first published 26 September 2020
Summary author Jasmine Catmull, BSI Marketing & Communications Officer