A new study explores the interactions between airway cells and immune cells at the molecular level to identify why some people are at risk of severe COVID-19 while others are not.
There is plenty of evidence that SARS-CoV-2, the new coronavirus, affects individuals differently. About 80% of those who have SARS-CoV-2 experience a clinically mild version of COVID-19, meaning that they get better without needing to go to the hospital.
Risk factors for severe disease include being male, being older, and having underlying health conditions, among other factors.
What drives these risk factors is not entirely clear.
Some experts have suggested that an excessive immune reaction in response to the virus is at the heart of the damage to the lungs and other parts of the body that people with severe COVID-19 experience.
Writing in Nature Biotechnology, scientists from the Center for Digital Health at the Berlin Institute of Health (BIH) and the Charité – Universitätsmedizin Berlin in Germany aimed to tease out the molecular actions that underpin such excessive immune reactions.
Prof. Roland Eils, chair and founding director of the Center for Digital Health, is one of the five senior study authors.
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Analyzing individual cells
To pinpoint how different cells interact and communicate with each other, the multidisciplinary research team performed a single cell RNA sequencing analysis of upper and lower respiratory tract samples from 19 people in the hospital with COVID-19 and five volunteers without the new coronavirus.
In total, the scientists analyzed 160,528 individual cells.
Of the 19 people with COVID-19, eight had moderate disease, the authors write, while they classed 11 as critical. Two people died from the disease.
In the participants with COVID-19, the team saw a three-fold increase in gene expression of the angiotensin converting enzyme 2 (ACE2) gene, which encodes the receptor that the new coronavirus uses to attach to cells during infection.
“It is interesting to note that in the case of COVID-19, the signaling protein interferon, which is actually the immune system’s central defense strategy against viral infections, contributes to the epithelial cells producing more ACE2 and hence becoming more vulnerable to viral infection,” Prof. Irina Lehmann, head of the Molecular Epidemiology Research Group at the BIH and one of the study’s senior authors, explains.
“In COVID-19, the immune system thus helps the virus to infect further cells, thereby amplifying the disease,” she continues.
Next, the team identified the specific subsets of epithelial and immune cells that were present in the samples and found proinflammatory cell types that may be driving cell death in the lungs.
“Especially in severely ill patients, we observed that an overreactive immune system drives the destruction of the lung tissue. This might explain why these patients are more severely affected by the infection than patients in whom the immune system reacts appropriately.”
– Prof. Roland Eils, corresponding author
Professor Leif-Erik Sander, another of the study senior authors, also weighs in on the findings:
“These results suggest that our treatments in COVID-19 patients should not only be directed against the virus itself but should also consider therapies that constrain the immune system, such as those now being used with dexamethasone, possibly even at the onset of the disease to prevent the immune system from overreacting.”
Specifically, the researchers suggest that targeting the proinflammatory “CCR1 and/or CCR5 pathways might suppress immune hyperactivation.”
The team acknowledges that their study has some shortcomings. Due to the relatively low number of people with COVID-19 who required hospital care in Germany, the study was not large enough to look at the influences of age, sex, and underlying health conditions on the results.
The researchers were also not able to include people who had mild COVID-19 and did not require hospital care.
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