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Cambridge Stem Cell Institute

Immune test. Credit: Imperial College London

Scientists in Cambridge and London have discovered novel immune responses that help explain how some individuals avoid getting COVID-19.


Using single-cell sequencing, researchers from the Wellcome Sanger Institute, University College London (UCL) and Imperial College London (ICL), the Netherlands Cancer Institute and their collaborators, studied immune responses against SARS-CoV-2 infection in healthy adult volunteers, as part of the COVID-19 human challenge study. Not all exposed participants went on to develop a COVID-19 infection, allowing the team to uncover unique immune responses associated with resisting sustained viral infection and disease.


The findings, published yesterday (19 June) in Nature, provide the most comprehensive timeline to date of how the body responds to SARS-CoV-2 exposure (or any infectious disease). The work is part of the Human Cell Atlas initiative to map every cell type in the human body.


Professor Sarah Teichmann, senior author of the study, formerly at the Wellcome Sanger Institute, Co-founder of the Human Cell Atlas and now based at the Cambridge Stem Cell Institute at the University of Cambridge, said: “As we’re building the Human Cell Atlas we can better identify which of our cells are critical for fighting infections and understand why different people respond to coronavirus in varied ways. Future studies can compare with our reference dataset to understand how a normal immune response to a new pathogen compares to a vaccine-induced immune response.”


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions across the globe with Coronavirus disease 2019 (COVID-19). While it is potentially fatal, many will have encountered someone who has tested positive for COVID-19, but have managed to avoid getting ill themselves, whether remaining negative on PCR testing or having an asymptomatic case of the disease.


While previous studies have examined COVID-19 patients after symptom onset, researchers set out to for the first time capture immune responses right from exposure.


In the UK COVID-19 Human Challenge, 36 healthy adult volunteers without previous history of COVID-19 were administered SARS-CoV-2 virus through the nose. Researchers performed detailed monitoring in the blood and lining of their noses, tracking the entire infection as well as the immune cell activity prior to the infection event itself for 16 volunteers. The teams at the Wellcome Sanger Institute and University College London then used single-cell sequencing to generate a dataset of over 600,000 individual cells.


Across all participants, the team discovered previously unreported responses involved in immediate virus detection. This included activation of specialised mucosal immune cells in the blood and a reduction in inflammatory white blood cells that normally engulf and destroy pathogens.


Individuals who immediately cleared the virus did not exhibit a typical and widespread immune response, but mounted novel subtle innate immune responses. Researchers suggest high levels of a gene called HLA-DQA2 before exposure also helped people prevent a sustained infection from taking hold. In contrast, individuals who developed a sustained SARS-CoV-2 infection showed a quick immune response in the blood, but a slower immune response in the nose where the virus established itself. The researchers also identified a new group of infection ‘intermediates’, where low levels of virus were detected but an immediate immune reaction in the nose likely prevented the onset of a sustained infection.


The researchers further identified common patterns among activated T cell receptors, which recognise and bind to virus-infected cells. This offers insights into immune cell communication and potential for developing targeted T cell therapies against not just COVID-19, but other diseases.


Dr Rik Lindeboom, co-first and co-corresponding author of the study, now at the Netherlands Cancer Institute, said: “This was an incredibly unique opportunity to see what immune responses look like in adults with no prior history of COVID-19, in a setting where factors such as time of infection and comorbidities could be controlled.”


Dr Marko Nikolić, senior author of the study at UCL and Honorary Consultant in Respiratory Medicine, said: “These findings shed new light on the crucial early events that either allow the virus to take hold or rapidly clear it before symptoms develop. We now have a much greater understanding of the full range of immune responses, which could provide a basis for developing potential treatments and vaccines that mimic these natural protective responses.”


Image credit: Imperial College London

This article was adapted from a Wellcome Sanger Institute press release here.