[Wednesday, 18 December 2024] At the beginning of the COVID-19 pandemic, numerous studies had shown that COVID-19 patients with high levels of neutrophils, a key immune cell, presented with more severe disease and poor clinical outcomes. It was not clearly understood though how or why this was happening. A recently published study from Trinity researchers now sheds light on the role of neutrophils in COVID-19 and its contribution to the disease's progression. Their findings uncover potential mechanisms that could guide more effective treatments for severe COVID-19. The study has been published in the journal JCI Insight.
It highlights that severe COVID-19 is characterized by an increase in low-density neutrophils (LDNs), a specific type of immature and activated neutrophil, which correlates strongly with disease severity and oxygen dependence. These LDNs show impaired function, including reduced reactive oxygen species production and deficient NET formation. Intriguingly, while intracellular arginase-1 levels are elevated, its release is blocked, suggesting a potential therapeutic target. Finally, although neutrophils suppress T-cell proliferation, this effect is independent of arginase-1, indicating other immunosuppressive mechanisms are at play.
Despite being the most abundant immune cells, neutrophils have often been overlooked in research due to the difficulties in studying them. Recent advances, however, are helping us realize their critical role in various diseases, including viral infections, cancer, and autoimmune disorders.
However, in certain instances, neutrophils can malfunction, turning what should be a mild infection into a life-threatening disease, such as in COVID-19. Understanding how neutrophils control COVID-19 disease severity may help to identify new therapeutic interventions that improve clinical outcomes for these patients.
KEY FINDINGS
- Low-density neutrophils: The team found that neutrophils from patients with severe COVID-19 have increased levels of a type of abnormal neutrophil called low-density neutrophils (LDNs). In addition, neutrophils from severe patients behave and function differently than neutrophils from patients with mild COVID-19 disease. In severe cases, neutrophils are the most immature and dysfunctional, showing defective production of neutrophil extracellular traps (NETs) and reactive oxygen species (ROS), both of which are crucial for the immune response against the COVID-19 causing SARS-CoV-2 virus.
- Defective Arginase-1 Release: One of the most important and unexpected results was the inability of neutrophils from patients with severe COVID-19 to release arginase-1 (a key enzyme involved in suppressing the immune response) despite these cells having elevated intracellular levels of the enzyme. This finding was surprising because arginase-1 is typically released by neutrophils to help resolve inflammation, but in these patients, the lack of arginase-1 release could be contributing to ongoing immune dysfunction and prolonged inflammation. This defect in arginase-1 release persisted even in convalescent patients, suggesting a long-lasting impact of the disease.
- Dexamethasone's Role: While dexamethasone, a commonly used corticosteroid, is a standard treatment for severe COVID-19, the study found that it modestly inhibited the release of arginase-1 from neutrophils. This was surprising because while dexamethasone helps reduce inflammation, it may inadvertently contribute to the neutrophil dysfunction observed in these patients, complicating its role in treating severe COVID-19.
The study also shows that, even in convalescent patients, neutrophil dysfunction persists, particularly with elevated arginase-1 levels. This indicates that post-recovery care should consider monitoring immune function in patients who have had severe COVID-19, as lingering immune abnormalities could have long-term health effects or contribute to complications.
Dr Conor Finlay, Senior Research Fellow, School of Medicine, and senior author said:
"Our work shows the neutrophil, a rather tricky immune cell to study, and often ignored for this reason, might be the most important player in disease severity in COVID-19."
Professor Mark Little, Professor of Nephrology in the Trinity Kidney Centre and senior author said:
"This work has led us to go on and ask questions about the importance of low-density neutrophils not just in COVID-19 but in cancer, infection and autoimmunity."
Dr Amrita Dwivedi, postdoctoral fellow and joint-first author said,
"Findings from this study can have implications beyond COVID-19, providing insights into how severe infections affect neutrophil behaviour and vice versa."
Dr Aisling Ui Mhaonaigh, Research Fellow, School of Medicine, joint-first author said:
"'I am delighted to be first author on this paper just published in JCI insight, highlighting the importance of arginase in inflammation. Neutrophils are notoriously understudied in immunology and this paper contributes a novel insight into neutrophil biology in COVID-19. All those long hours in full PPE in the C19 lab has paid off, huge credit to all involved especially Amrita, Conor and Mark."
READ: You can read the full paper: Emergence of dysfunctional neutrophils with a defect in arginase-1 release in severe COVID-19 at this link: https://insight.jci.org/articles/view/171659 .
