Using single-cell sequencing technology, researchers provide the most comprehensive timeline to date of how the body responds to SARS-CoV-2 exposure.

Scientists 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), Imperial College London, the Netherlands Cancer Institute and their collaborators, studied immune responses against SARS-CoV-2 infection in healthy adult volunteers, as part of the world’s first COVID-19 human challenge study¹. 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 today (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 body².

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 come into contact with 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, in this new study researchers set out to capture immune responses right from exposure, in an immunologically naïve cohort for the first time.

As part of the UK COVID-19 Human Challenge study, led by Imperial College London, 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 UCL 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 virus³ did not show a typical widespread immune response but instead mounted subtle, never-seen-before innate immune responses. Researchers suggest high levels of activity of a gene called HLA-DQA2 before exposure also helped people prevent a sustained infection from taking hold. In contrast, the six individuals who developed a sustained SARS-CoV-2 infection exhibited a rapid immune response in the blood but a slower immune response in the nose, allowing the virus to establish itself there.

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.