Coronavirus particles, illustration - SARS-CoV-2 virus

Interferon gamma (IFN-γ) is a potential biomarker for Long COVID fatigue and this finding could be the basis for new therapies for the condition, a University of Cambridge-led study suggests. It’s known that SARS-CoV-2 triggers the production of the antiviral protein IFN-γ, which is associated with fatigue, muscle ache, and depression. This team’s work shows that in Long COVID patients, IFN-y production persists until symptoms improve, highlighting a potential biomarker and a target for therapies.

“We have found a potential mechanism underlying Long COVID which could represent a biomarker—that is, a tell-tale signature of the condition. We hope that this could help to pave the way to develop therapies and give some patients a firm diagnosis,” said co-author, Benjamin Krishna, from the Cambridge Institute of Therapeutic Immunology & Infectious Disease.

The study, published this week in Science Advances, followed a group of patients with Long COVID fatigue for over 2.5 years, to understand why some recovered and others did not.

Long COVID continues to affect millions of people globally and is placing a major burden on health services. An estimated 1.9 million people in the U.K. alone (2.9% of the population) were experiencing self-reported Long COVID as of March 2023, according to the U.K.’s Office of National Statistics (ONS). Fatigue is the most common symptom.

IFN-γ production is a normal reaction to COVID infection from the immune system. For most people, when their infection clears, COVID-19 symptoms cease and production of this protein stops. But these researchers found that high levels of IFN-γ persisted in some Long COVID patients for up to 31 months.

The study began in 2020 when Nyarie Sithole set up a Long COVID clinic in Cambridge’s Addenbrooke’s Hospital, where he started collecting blood samples from patients and set about studying their immunology.  

“When the clinic started, a lot of people didn’t even believe Long COVID was real,” 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 team recruited 55 Long COVID patients—all experiencing severe symptoms at least five months after acute COVID-19—attending Addenbrooke’s Long COVID clinic. By analyzing blood samples. The team found that the white blood cells of individuals infected with SARS-CoV-2 produced IFN-γ, and that this persisted in Long COVID patients.

Krishna said: “Interferon gamma can be used to treat viral infections such as hepatitis C but it causes symptoms including fatigue, fever, headache, aching muscles and depression. These symptoms are all too familiar to Long COVID patients. For us, that was another smoking gun.”

Using ‘cell depletion assays’, the team managed to identify the precise cell types responsible for producing IFN-γ. They pinpointed CD8+ T cells but found that these required contact with another immune cell type: CD14+ monocytes.

The Cambridge team followed its Long COVID cohort for up to 31 months post-infection. During this follow-up period, over 60% of patients experienced resolution of some, if not all, of their symptoms which coincided with a drop in IFN- γ.

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