Fatigue, muscle ache, and depression—hallmarks of Long COVID—may be linked to persistently elevated levels of an antiviral protein called interferon gamma (IFN-γ), according to a new study from the University of Cambridge. The research, published in Science Advances, offers a potential biomarker for the condition and a new avenue for developing targeted therapies, while also providing valuable insight as the world prepares for potential future pandemics.
For millions worldwide, the debilitating effects of Long COVID continue long after the initial SARS-CoV-2 infection has cleared. An estimated 1.9 million people in the UK alone—roughly 2.9% of the population—were experiencing self-reported Long COVID as of March 2023, according to the Office for National Statistics. The study focused on fatigue, the most commonly reported and often most disabling symptom, and sought to understand why some individuals recover while others remain ill for months, even years.
Researchers followed 111 patients who had confirmed COVID-19 infections, analyzing blood samples taken at 28, 90, and 180 days after symptom onset. A subset of 55 patients experiencing severe symptoms at least five months after their initial infection were recruited from the Long COVID clinic at Addenbrooke’s Hospital in Cambridge between August 2020 and July 2021. The team discovered that in some individuals, IFN-γ production didn’t subside after the acute infection resolved, persisting for up to 31 months.
The Role of IFN-γ in Long COVID
IFN-γ is a naturally occurring protein produced by the immune system in response to viral infections. While crucial for fighting off viruses, the study suggests that its prolonged presence in some patients may contribute to the ongoing symptoms of Long COVID. “We have found a potential mechanism underlying Long COVID which could represent a biomarker – that is, a tell-tale signature of the condition,” explained Dr. Benjamin Krishna, a co-author of the study from the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID). “We hope that this could aid to pave the way to develop therapies and give some patients a firm diagnosis.”
The research team pinpointed the source of the persistent IFN-γ production to CD8+ T cells, a type of immune cell, but found these cells required interaction with another immune cell type, CD14+ monocytes, to maintain the elevated levels. This discovery provides a more precise understanding of the immunological processes at play in Long COVID, moving beyond earlier observations of simply elevated IFN-γ levels.
Vaccination and Symptom Resolution
Interestingly, the study also revealed a link between vaccination and symptom improvement. Researchers observed a significant decrease in IFN-γ levels after vaccination in patients whose Long COVID symptoms resolved. “If SARS-CoV-2 continues to persist in people with Long COVID, triggering an IFN-γ response, then vaccination may be helping to clear this,” Dr. Krishna noted. “But we still necessitate to find effective therapies.”
The findings suggest that vaccination may play a role in reducing the viral reservoir and, lowering the persistent immune activation that drives Long COVID symptoms. However, Dr. Krishna cautioned that new cases continue to emerge, and understanding the underlying mechanisms of Long COVID is crucial for preparing for future coronavirus pandemics.
Beyond Microclotting: A More Complete Picture
While some previous research has focused on microclotting as a potential cause of Long COVID, the Cambridge study suggests that IFN-γ dysregulation may be a more central factor, though it doesn’t rule out a role for microclotting entirely. The team argues that the presence of IFN-γ could be used to classify Long COVID into subtypes, allowing for more personalized treatment approaches. “It’s unlikely that all the different Long COVID symptoms are caused by the same thing,” Dr. Krishna said. “We need to differentiate between people and tailor treatments. Some patients are slowly recovering and there are those who are stuck in a cycle of fatigue for years on end. We need to grasp why.”
The research began in 2020 when Dr. Nyarie Sithole established a Long COVID clinic at Addenbrooke’s Hospital, recognizing the need for dedicated research into this emerging condition. “When the clinic started, a lot of people didn’t even believe Long COVID was real,” Dr. Sithole said. “We are indebted to all the patients who volunteered for this study, without whose support and participation we would obviously not have accomplished this study.”
The study’s findings offer a promising step forward in unraveling the complexities of Long COVID. Researchers are now focused on developing therapies that target the persistent IFN-γ response, potentially offering relief to the millions affected by this debilitating condition. Further research will be needed to fully understand the long-term implications of sustained IFN-γ production and to identify individuals most likely to benefit from targeted interventions.
Disclaimer: This article provides information for general knowledge and informational purposes only, and does not constitute medical advice. It is essential to consult with a qualified healthcare professional for any health concerns or before making any decisions related to your health or treatment.
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