The immune response to the SARS-CoV-2 virus and mechanisms underlying severe COVID-19
“The main way for the immune system to identify viruses is through a specialised set of proteins, which display parts of the virus on the surface of the infected cell. Immune cells recognise the displayed pieces of the virus and kill the infected cell. In this way the spread of the virus is halted. However, the immune system may act so vigorously that this reaction is what really causes disease. This is part of the problem in severe COVID-19,” said STIAS fellow Edvard Smith of the Department of Laboratory Medicine at the Karolinska Institutet, Stockholm, Sweden.
Smith took STIAS fellows through a detailed unravelling of the complex world of viruses and the body’s response to them.
He explained that the original discovery of viruses is generally attributed to Dmitry Ivanovsky, a Russian microbiologist who identified the tobacco mosaic disease virus in 1892. Viruses contain either RNA or DNA with COVID-19 containing RNA.
There are large numbers of coronaviruses but the main ones affecting humans are Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS) and SARS-CoV-2 or COVID-19. They all move from their natural hosts to intermediate hosts then into humans. “SARS-CoV-2 is not the most lethal – the SARS outbreak in 2003 and MERS in 2012 had higher mortality rates.”
However, COVID-19 is a particularly effective virus. It contains 30 000 nucleotides (building blocks) in comparison to Hepatitis B, for example, which has only 3000. This means you don’t need huge amounts of virus to infect. “Each infected individual carries approximately 109 to 1011 virus particles – a total mass of about 100 micrograms. One billion people would have about 100 kg of virus particles – so it is extremely effective – you don’t need much in terms of weight.”
“Viruses are special microorganisms,” said Smith. “They have no metabolism outside their host, but come to life once they infect and take over cells. For the immune system viruses represent a challenge because once they infect cells they are sheltered and not visible. Only once they leave the cell as virus particles and infect other cells can they be recognised by antibodies.”
Smith explained the different components of the virus as well as the mechanics of how the COVID-19 viral particles enter host cells via the angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed in various human organs, then proceed to hijack those cells.
“The ACE2 receptor has been shown to be crucial for infection,’ he said. “The virus binds to ACE2 and is either engulfed or becomes fused to the cell membrane. Virus particles are then produced in large quantities and break away to infect other cells.”
“The different COVID-19 variants have different fusion capacity,” he added. “The Delta variant, which now predominates globally, has faster fusion with the receptor and is also able to make more virus particles in the cell once fused.”
Fighting back
Smith then explained the workings of the immune system to fight intruders – in particular the role of antibodies and T cells. Antibodies are proteins that bind to foreign antigens. They are produced by B lymphocytes (white blood cells) with each producing about 2000 antibodies with different specificities in their most mature form, the plasma cell.
“Antibodies can attack intruders both before they enter the cells and once the virus particles are released. They are particularly effective against bacteria, which normally reside outside cells.”
“But we also need T lymphocytes – these are our major defence against viruses. Using antigen-presenting mechanisms they are able to look inside a cell and kill virus-infected cells thus halting the spread. If you don’t have working T cells, you cannot destroy viruses.”
Innate immunity also involves macrophages, granulocytes and interferons. Interferons are particularly important and include three types – interferon a, b and g with Interferon a proving important in COVID-19. A deficient interferon response results in the most severe forms of COVID-19.
So, why do some people get so sick?
The severity of COVID-19 infection is dependent on many factors including the initial virus dose (viral load); the strength of the immune system response which is affected by age and other underlying conditions (many of the deaths in the first and second waves were in people with cancers like leukaemia); as well as mutations in the genes of components of the immune system. For example, variations in the toll-like receptor 7 which is essential for protection against COVID-19 have been found in 1.8% of men under 60 who end up in ICU due to COVID-19. Toll-like receptors are crucial components in the initiation of innate immune responses to various pathogens, causing the production of pro-inflammatory cytokines and interferons.
Autoantibodies (antibodies produced by the immune system that are directed against the body’s own proteins and cause many autoimmune diseases) have also been shown to play an important role in COVID-19 infection with hospitalised patients much more likely to have autoantibodies.
“Autoantibodies that are directed against interferons are a big risk accounting for 20% of deaths in males older than 70 years,” said Smith.
Smith explained that these factors and others not yet known mean COVID-19 infection can result in the immune system overreacting leading to an aggressive inflammatory response with the release of excessive pro-inflammatory cytokines in an event known as ‘cytokine storm’ which can affect all organs, as well as cause disseminated intravascular coagulation, which disrupts the body’s normal blood-clotting process resulting in excessive simultaneous clotting and bleeding.
“So you can get severe COVID-19 illness from both an insufficient and an over-reacting immune system,” he said.
In discussion, Smith addressed the rising rate of infection currently in most European countries as well as why some regions of the world appear to be less affected than others.
“Underreporting is a factor, of course, but it’s also possible that other coronaviruses may have been around longer and people have had longer exposure in some parts of the world. Weather also plays a role – infection rates are higher during winters with low temperatures – in areas of the world with year-round summer this must be a factor.”
“There is no question that we have been extremely fortunate on two issues – the variant and the vaccine,” he said. “If the initial virus in circulation had been the Delta variant we would have had a much higher mortality rate – probably more than ten times. Vaccine research has, during recent years, not been a highly thought of area of science but, because of the work already done on vaccines – especially mRNA vaccines, it was possible to build on existing knowledge to produce a vaccine in record time. Without these factors there would have been many more casualties.”
“Everyone should vaccinate,” he concluded. “The unvaccinated have a much higher risk of dying if they contract the infection. There is also an urgent need to distribute vaccines more evenly globally. Keeping infection numbers as low as possible across the world protects everyone because it also reduces the likelihood of new, more infectious variants occurring.”
Michelle Galloway: Part-time media officer at STIAS
Photograph: Noloyiso Mtembu