Immune responses of people with asymptomatic and severe Covid-19 compared by Cambridge scientists
Differences in the immune response to Covid-19 between people with no symptoms and those with a more serious reaction to the virus have been analysed in the largest study of its kind in the UK.
The research – involving the Wellcome Sanger Institute and its Hinxton neighbour, the EMBL European Bioinformatics Institute (EMBL-EBI), along the University of Cambridge and others – found raised levels of specific immune cells in asymptomatic people.
They discovered that those with more serious symptoms had lost these protective cell types, but had gained inflammatory cells, a finding that helps explain the serious lung inflammation and blood clotting symptoms seen in these patients.
Prof Menna Clatworthy, senior author and professor of translational immunology at the University of Cambridge and Wellcome Sanger Institute associate faculty, said: “This is one of the most detailed studies of immune responses in Covid-19 to date, and begins to help us understand why some people get really sick while others fight off the virus without even knowing they have it. This new knowledge will help identify specific targets for therapy for patients that get sick with Covid-19.”
The large-scale collaborative project was one of the only studies so far to include people who were asymptomatic. Also involving Newcastle University and University College London, it was part of the Human Cell Atlas initiative, which is mapping every cell type in the human body.
Several previous studies have shown a complex immune response to the SARS-CoV-2 virus in the blood. But until now, the body’s full co-ordinated immune response and how it differs between symptomatic and asymptomatic patients had not been investigated in detail.
The researchers analysed blood from 130 people with Covid-19 from Cambridge, London and Newcastle.
Single-cell sequencing from around 800,000 individual immune cells was carried out, along with detailed analysis of cell surface proteins and antigen receptors found on immune cells in the blood.
Increased levels of protective B cells that produce antibodies found in mucus passages, such as the nose, were found in those with no symptoms. These antibodies could be one of our first lines of defence in Covid-19.
These B cells were missing in those with serious symptoms, demonstrating the importance of an effective antibody-associated immune response in the nose and other mucus passages.
Likewise, while patients with mild to moderate symptoms had high levels of B cells and helper T-cells that fight infection, many of these cells had been lost in those with serious symptoms, suggesting this part of the immune system had failed in those with severe disease.
The research, published in Nature Medicine, found those with more serious symptoms leading to hospitalisation had an uncontrolled increase in monocytes and killer T-cells. High levels of these can lead to lung inflammation.
Patients with severe disease also had raised levels of platelet-producing cells, which promote blood clotting.
Prof Muzlifah Haniffa, senior author from Newcastle University and senior clinical fellow at the Wellcome Sanger Institute, said: “This is one of the only studies of its kind that looks at samples collected from asymptomatic people, which helps us start to understand why some people react differently to Covid-19 infection.
“It could also explain symptoms such as lung inflammation and blood clots. The immune system is made up of lots of different groups of cells, similar to the way an orchestra is made up of different groups of instruments, and in order to understand the co-ordinated immune response, you have to look at these immune cells together.”
It is not yet understood how the infection stimulates these various immune responses.
But it does offer a molecular explanation for how Covid-19 increases the risk of blood clotting and inflammation in the lungs – a problem that can lead to patients requiring a ventilator.
Further research could lead to the development of treatments that decrease platelet production or cut the number of killer T-cells produced.
And examining levels of these immune cells in a patient’s blood could help identify those who are more likely to experience moderate to severe disease.
The findings also hinted that the immune response may be tailored to, or affected by, variants of the virus, as the nature of the antibody response appeared to correlate to the person’s geographic area.
Dr John Marioni, senior author and head of research at EMBL’s European Bioinformatics Institute (EMBL-EBI) and senior group leader at the Cancer Research UK Cambridge Institute, said: “Using data from three different centres has allowed us to look at how people react to Covid-19 throughout the UK. The amount of data collected in this study has given us crucial insight into the immune reaction in various different severities of Covid-19 infection.”
It is at the Wellcome Sanger Institute that much of the country’s sequencing of Covid-19 samples is carried out, to help us keep track of the spread of variants.
Prof Berthold Göttgens, senior author and professor of molecular haematology at the University of Cambridge, said: “Along with the findings, the way this study was conducted is noteworthy, as it was a new way of doing biomedical science.
“By bringing different experts together, we were able to employ a divide and conquer approach, which allowed us to complete the work in extra quick time.
“This study required a large teamwork effort, in the middle of the pandemic when labs were being shut down. This was an incredibly rewarding study to work on, with everyone understanding the importance of the work and willing to go the extra mile.”
Dr Sarah Teichmann, senior author from the Wellcome Sanger Institute and co-chair of the Human Cell Atlas organising committee, said: “This is a great example of using the Human Cell Atlas to understand Covid-19 and identify which of our cells are critical for infection and treatment.
“This information can be used to better understand why different people react to coronavirus in different ways. The data is openly accessible and can provide a basis for developing potential new therapies, to reduce the spread of the virus, or to protect those who start to develop severe disease.”
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