Study Reveals Immune Factors Behind COVID-19 Resistance in Some Individuals

As part of the first-ever COVID-19 human challenge study, researchers from the Wellcome Sanger Institute, University College London (UCL), Imperial College London, the Netherlands Cancer Institute, and their collaborators examined immune responses against SARS-CoV-2 infection in healthy adult volunteers using single-cell sequencing.

Not every exposed individual went on to contract COVID-19, which allowed the researchers to identify distinct immune reactions linked to fending off long-term viral infection and illness.

The results, published in the journal Nature, offer the most thorough chronology of the body's reaction to an infectious disease, including SARS-CoV-2 exposure to date. The effort to map every type of cell in the human body is known as the Human Cell Atlas.

Millions of people worldwide are afflicted with Coronavirus disease 2019 (COVID-19) thanks to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many people have come in touch with someone who has tested positive for COVID-19, despite the fact that it can be fatal, yet have avoided becoming ill themselves by either having an asymptomatic case of the disease or remaining negative on PCR testing.

While earlier research focused on COVID-19 patients after symptoms appeared, the current study aimed to record immune responses as soon as possible in a group that was immunologically naïve.

As part of the Imperial College London-led UK COVID-19 Human Challenge research, the SARS-CoV-2 virus was injected through the nose into 36 healthy adult volunteers who had never had COVID-19.

For 16 volunteers, researchers monitored their blood and nasal lining in great detail, following the course of the illness and the immune cells' activity before the infection actually occurred. Then, using single-cell sequencing, the Wellcome Sanger Institute and UCL teams produced a dataset of over 600,000 individual cells.

The team found previously unreported reactions involved in real-time viral detection across all individuals. This included a decrease in inflammatory white blood cells, which typically engulf and eliminate infections, and activation of specialized mucosal immune cells in the blood.

Those who immediately eliminated the virus developed modest, previously unseen innate immune responses rather than the usual extensive immune response. According to research, those who had high levels of HLA-DQA2 gene activity prior to exposure were also less likely to become very ill from a persistent illness.

On the other hand, six people who experienced a persistent infection with SARS-CoV-2 showed a quick immune response in their bloodstream but a delayed one in their noses, which allowed the virus to take hold there.

The researchers also discovered shared patterns among T cell receptors that have been activated, which are able to recognize and attach to virus-infected cells. This provides information on immune cell communication and raises the possibility of creating targeted T-cell treatments not only for COVID-19 but also for other illnesses.

This was an incredibly unique opportunity to see what immune responses look like when encountering a new pathogen – 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. Rik Lindeboom, Study Co-First Author, Netherlands Cancer Institute

Dr. Marko Nikolić, Study Senior Author from 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.”

As we are 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.”

Dr. Sarah Teichmann, Study Author and Co-Founder, Human Cell Atlas

Teichmann is now based at the Cambridge Stem Cell Institute, University of Cambridge.

Balasinga said, “Human challenge models are an invaluable way to build our understanding of how the body responds to infectious disease. These studies enable us to closely monitor what happens from the moment of infection by allowing us to follow the immune response through to the development and severity of symptoms.”

These results are an exciting addition to our evidence-base of how different people might respond to, or be protected against, COVID-19 infections. We need to understand how factors like natural exposure to the disease affect the body’s response to the virus or a vaccine. Therefore, it is crucial studies like this expand to low-resource settings where diseases are endemic, to ensure we are developing context-specific tools and therapeutics that work for those most vulnerable.”

Shobana Balasinga, Research Lead, Infectious Disease Team, Wellcome Sanger Institute

Source:
Journal reference:

Lindeboom, R. G. H., et al. (2024) Human SARS-CoV-2 challenge uncovers local and systemic response dynamics. Nature. doi.org/10.1038/s41586-024-07575-x.

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