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Tuesday, 26 Dec, 2023
Mast cells under spotlight for role in COVID lung injury
In a breakthrough that brings hope to people at risk of severe COVID-19, scientists at Duke-NUS Medical School have identified the driver behind some of the most serious COVID-19 complications, including pneumonia, breathlessness as well as potentially fatal cardiovascular events like blood clots and strokes. Their findings, published in the Journal of Clinical Investigation, identified a type of immune cell called mast cells as the culprit, pointing to new therapeutic targets for preventing pneumonia and acute respiratory distress syndrome seen in the most vulnerable patients.
Mast cells are a type of immune cell that acts as a first responder for the immune system. These cells play a vital role in detecting and clearing foreign substances including viruses and bacteria but can become overactivated. When that happens, they drive fluid build-up, bleeding and other lung damage.
Yet despite their widespread presence and relatively large size, these immune cells have largely been overlooked as scientists raced to decode how the immune system responds to SARS-CoV-2 infection.
Using preclinical models of COVID-19, the international team of scientists led by Associate Professor Ashley St John from Duke-NUS’ Emerging Infectious Diseases Programme, uncovered that widespread activation of mast cells coincided with fluid build-up, bleeding and other severe lung damage, resembling the most serious complications seen in humans.
“Our results show that mast cells are essential contributors to the severe lung damage induced by SARS-CoV-2 infection,” said first author Ms Janessa Tan, a research assistant in Assoc Prof St John’s lab at Duke-NUS. “Targeting mast cell activation may represent a viable approach to reduce harmful inflammation and improve patient outcomes.”
Analysis of blood samples from COVID-19 patients confirmed the link between mast cell hyperactivity and disease severity. Levels of a mast-cell product called chymase were significantly higher in patients with severe COVID-19 compared with mild cases or healthy individuals.
“This study sheds new light on the immune mechanisms driving COVID-19 severity and long-term complications,” said Assoc Prof St John, who is the senior author. “It sets the stage for investigating mast cell-stabilising drugs as an intervention to prevent severe lung damage in patients.”
Through their analysis of the human mast cell response at both the protein and gene-expression level, the scientists were also able to implicate mast cells in driving the severe vascular effects of COVID-19.
“COVID-19 can result in patients requiring hospitalisation due to pneumonia, but it also causes blood clots, strokes and cardiovascular events that can turn fatal. Our study suggests that mast cells may connect the lung and vascular pathologies through their influence on inflammation, clotting and vessel integrity,” said Assoc Prof St John, who collaborated on this study with colleagues from Australia, Singapore, including the National University of Singapore and Singapore General Hospital, as well as Duke University Medical Centre in the United States.
“This breakthrough by Ashley St John and her collaborators could benefit many vulnerable individuals who are at risk of severe COVID-19. A mast cell-focused intervention could not only alleviate the severity of disease but remain an effective tool in our arsenal even as the virus continues to evolve. This is another important piece in the COVID puzzle that has the potential to save lives and further reduce the pressures on hospital resources,” said Senior Vice-Dean for Research Professor Patrick Tan.
What happens when mast cells remain active // Credit: Duke-NUS COVID Stories
A phase III clinical trial, initiated in collaboration with Duke-NUS, Duke University School of Medicine and Sen-Jam Pharmaceutical Partners, is underway. The trial is investigating the use of an already licensed mast cell-stabilising drug in combination with a non-steroidal anti-inflammatory drug on severe COVID-19. The trial is underway in Nepal with results expected in 2024.
“Hopefully, this discovery can improve outcomes for vulnerable patients who still need to be hospitalised because of the severity of their infection,” said Assoc Prof St John, who hopes to bring additional trial sites to the ongoing clinical trial so that they can further speed up recruitment of eligible patients.