The largest study of its type in the UK has identified differences in the immune response to COVID-19 between asymptomatic people and those suffering more severely with the virus.
Researchers at the Cambridge Stem Cell Institute are part of a team working across the University of Cambridge, Wellcome Sanger Institute, Newcastle University, University College London and EMBL’s European Bioinformatics Institute (EMBL-EBI), who have found raised levels of specific immune cells in asymptomatic people with COVID-19.

They also showed people with more serious symptoms had lost these protective cell types, but gained inflammatory cells. These differences in the immune response could help explain serious lung inflammation and blood clotting symptoms, and could be used to identify potential targets for developing therapies.

The research, published today in Nature Medicine, is one of the only studies to include people who were asymptomatic.

So far, the COVID-19 pandemic has caused millions of deaths and many more infections worldwide. Symptoms vary widely in severity and can range from a mild cough to severe respiratory distress, blood clots and organ failure. Several previous studies have highlighted a complex immune response in the blood, but until now the full coordinated immune response and how this differs between symptomatic and asymptotic patients had not been investigated in detail.

In this new study to understand how different immune cells responded to the infection, a large team of researchers came together to analyse blood from 130 people with COVID-19. These patients came from three different UK centres (Newcastle, Cambridge and London) and ranged from asymptomatic to critically severe.

Dr Fernando Calero Nieto, one of the joint first authors of the paper and Senior Research Associate at the Cambridge Stem Cell Institute, said: “This project was an extraordinary collective effort. Our group was able to share our experience in single-cell genomic techniques to help analyse patient samples collected by NHS staff in Cambridge in collaboration with colleagues at the Cambridge Institute for Therapeutic Immunology and Infectious Disease.”

“We simultaneously measured 188 cell surface markers and whole transcriptomes in nearly 800,000 individual blood cells from 130 patients, including T- and B-cell receptor rearrangements. The published dataset is an unparalleled resource for anyone studying COVID-19, or wanting to develop therapeutics.”

The team performed single-cell sequencing from ~800,000 individual immune cells, along with detailed analysis of cell surface proteins and antigen receptors found on immune cells in the blood. They revealed differences in multiple types of immune cells that are involved in the body’s response to COVID-19.

In those with no symptoms, the team found increased levels of B cells that produce antibodies that are found in mucus passages, such as the nose. These antibodies may be one of our first line of defence in COVID-19. However, these protective B cells were missing in people with serious symptoms, indicating the importance of an effective antibody-associated immune response at the nose and other mucus passages.

The team discovered that whereas patients with mild to moderate symptoms, had high levels of B cells and helper T-cells, which help fight infection, those with serious symptoms had lost many of these immune cells, suggesting that this part of the immune system had failed in people with severe disease.

In contrast, people with more serious symptoms leading to hospitalisation had an uncontrolled increase in monocytes and killer T-cells, high levels of which can lead to lung inflammation. Those with severe disease also had raised levels of platelet-producing cells, which help blood to clot.

Professor Muzlifah Haniffa, a 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 coordinated immune response, you have to look at these immune cells together.”

While it is not yet understood how the infection stimulates these immune responses, the study gives a molecular explanation for how COVID-19 could cause an increased risk of blood clotting and inflammation in the lungs, which can lead to the patient needing a ventilator. This also uncovers potential new therapeutic targets to help protect patients against inflammation and severe disease.

For example, it may be possible to develop treatments that decrease platelet production or reduce the number of killer T-cells produced, however more research is required.

Professor Menna Clatworthy, a senior author and Professor of Translational Immunology at the University of Cambridge and Sanger 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.”

In the future, research may identify those who are more likely to experience moderate to severe disease by looking at levels of these immune cells in their blood.

This study used samples from three centres in the UK, and found that some antibody responses were similar in individuals in one geographic area compared with those at a different centre, hinting that this part of the immune response may be tailored to different variants of the virus.

Professor Bertie Göttgens, a senior author, Group Leader at the Cambridge Stem Cell Institute 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.”

This collaborative effort at the Cambridge Stem Cell Institute extended throughout our home at the Jeffrey Cheah Biomedical Centre and on the Cambridge Biomedical Campus.

The Göttgens and Laurenti Groups worked closely with the Cambridge Institute for Therapeutic Immunology and Infectious Disease, including Professor Ken Smith and Dr Paul Lyons. They received greatly-appreciated support from facilities staff, laboratory suppliers and the Cancer Research UK Cambridge Institute genomics core facility through Dr Paul Coupland.