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Recent research has identified novel immune responses that help explain why some individuals avoid contracting COVID-19 despite exposure. Utilizing single-cell sequencing, scientists from the Wellcome Sanger Institute, University College London (UCL), Imperial College London, and the Netherlands Cancer Institute conducted an in-depth study on immune responses to SARS-CoV-2 in healthy adult volunteers. This work was part of the world's first COVID-19 human challenge study and was published on June 19 in Nature.
Comprehensive Study on SARS-CoV-2 Immune Response
The research aimed to capture immune responses from the initial exposure to the SARS-CoV-2 virus in immunologically naïve individuals. As part of the UK COVID-19 Human Challenge study, 36 healthy adults without prior COVID-19 history were exposed to the virus through their nasal passages. The researchers meticulously monitored immune responses in the blood and nasal lining of these volunteers, generating a dataset of over 600,000 individual cells using single-cell sequencing.
Dr. Rik Lindeboom, co-first author from the Netherlands Cancer Institute, emphasized the uniqueness of this opportunity: “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.”
Discovery of Unique Immune Responses
The study revealed previously unreported immediate virus detection responses. Notably, it identified the activation of specialized mucosal immune cells in the blood and a reduction in inflammatory white blood cells, typically involved in pathogen destruction. Some participants who immediately cleared the virus did not exhibit the usual widespread immune response but showed subtle, unique innate immune responses. High activity levels of the gene HLA-DQA2 before exposure were suggested to play a role in preventing sustained infection.
In contrast, individuals who developed a sustained infection showed a rapid immune response in the blood but a slower response in the nasal passages, allowing the virus to establish itself there. The researchers also identified common patterns among activated T cell receptors, providing insights into immune cell communication and the potential for developing targeted T cell therapies for COVID-19 and other diseases.
Dr. Marko Nikolić, senior author from UCL, stated, “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.”
Implications for Future Research and Therapies
The study contributes significantly to the Human Cell Atlas initiative, which aims to map every cell type in the human body. Dr. Sarah Teichmann, co-founder of the Human Cell Atlas, highlighted the importance of this work: “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.”
The findings underscore the value of human challenge models in understanding immune responses to infectious diseases. Shobana Balasingam from Wellcome's Infectious Disease team remarked on the broader implications of the study: “Human challenge models are an invaluable way to build our understanding of how the body responds to infectious disease... 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.”
Publication Details
Lindeboom, R.G.H., Worlock, K.B., Dratva, L.M. et al. Human SARS-CoV-2 challenge uncovers local and systemic response dynamics. Nature (2024). https://doi.org/10.1038/s41586-024-07575-x
Comprehensive Study on SARS-CoV-2 Immune Response
The research aimed to capture immune responses from the initial exposure to the SARS-CoV-2 virus in immunologically naïve individuals. As part of the UK COVID-19 Human Challenge study, 36 healthy adults without prior COVID-19 history were exposed to the virus through their nasal passages. The researchers meticulously monitored immune responses in the blood and nasal lining of these volunteers, generating a dataset of over 600,000 individual cells using single-cell sequencing.
Dr. Rik Lindeboom, co-first author from the Netherlands Cancer Institute, emphasized the uniqueness of this opportunity: “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.”
Discovery of Unique Immune Responses
The study revealed previously unreported immediate virus detection responses. Notably, it identified the activation of specialized mucosal immune cells in the blood and a reduction in inflammatory white blood cells, typically involved in pathogen destruction. Some participants who immediately cleared the virus did not exhibit the usual widespread immune response but showed subtle, unique innate immune responses. High activity levels of the gene HLA-DQA2 before exposure were suggested to play a role in preventing sustained infection.
In contrast, individuals who developed a sustained infection showed a rapid immune response in the blood but a slower response in the nasal passages, allowing the virus to establish itself there. The researchers also identified common patterns among activated T cell receptors, providing insights into immune cell communication and the potential for developing targeted T cell therapies for COVID-19 and other diseases.
Dr. Marko Nikolić, senior author from UCL, stated, “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.”
Implications for Future Research and Therapies
The study contributes significantly to the Human Cell Atlas initiative, which aims to map every cell type in the human body. Dr. Sarah Teichmann, co-founder of the Human Cell Atlas, highlighted the importance of this work: “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.”
The findings underscore the value of human challenge models in understanding immune responses to infectious diseases. Shobana Balasingam from Wellcome's Infectious Disease team remarked on the broader implications of the study: “Human challenge models are an invaluable way to build our understanding of how the body responds to infectious disease... 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.”
Publication Details
Lindeboom, R.G.H., Worlock, K.B., Dratva, L.M. et al. Human SARS-CoV-2 challenge uncovers local and systemic response dynamics. Nature (2024). https://doi.org/10.1038/s41586-024-07575-x