Home Medizin Identifizierung des antiviralen Proteins IFN-γ als potenzieller Biomarker für Long COVID

Identifizierung des antiviralen Proteins IFN-γ als potenzieller Biomarker für Long COVID

von NFI Redaktion

SARS-CoV-2 triggers the production of the antiviral protein IFN-γ, which is associated with fatigue, muscle pain, and depression. New research shows that in Long-COVID patients, IFN-γ production persists until symptoms improve, making it a potential biomarker and target for therapies.

Identifying antiviral protein IFN-γ as a potential biomarker for Long COVID
Woman sitting in the dark on the sofa with a hand on her forehead. Image credit: Annie Spratt via Unsplash

A study conducted by the University of Cambridge identifies the protein Interferon-Gamma (IFN-γ) as a potential biomarker for Long-COVID fatigue and highlights an underlying immunological mechanism of the disease that could pave the way for the development of much-needed therapies and provide a lead in the event of a future coronavirus pandemic.

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

Long-COVID continues to affect millions of people worldwide, placing a significant burden on healthcare services. According to the ONS, an estimated 1.9 million people (2.9% of the population) in the UK alone had self-reported Long-COVID in March 2023. Fatigue remains the most common and debilitating symptom by far, and patients are still awaiting an effective treatment.

The study reveals that an initial infection with SARS-CoV-2 triggers the production of the antiviral protein IFN-γ, which is a normal immune response. In most individuals, COVID-19 symptoms subside along with the production of this protein once their infection has cleared. However, the researchers found that in some Long-COVID patients, high levels of IFN-γ persisted for up to 31 months.

„We have identified a potential mechanism underlying Long COVID and a biomarker that could represent a telltale signature of the disease. We hope this can help pave the way for the development of therapies and provide some patients with a safe diagnosis.“

Dr. Benjamin Krishna, Co-Author, Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID).

The research began in 2020 when Dr. Nyarie Sithole established a Long-COVID clinic at Addenbrooke’s Hospital in Cambridge, where he began collecting blood samples from patients and delving into their immunology. Sithole soon gained the support of Dr. Benjamin Krishna and Dr. Mark Wills from the University of Cambridge’s Medical School.

„When the clinic started, many people didn’t even believe that Long-COVID existed,“ said Dr. Sithole. „We owe all the patients who volunteered for this study a huge debt of gratitude, as without their support and participation, we wouldn’t have been able to conduct this study.“

The team analyzed 111 COVID-confirmed patients admitted to Addenbrooke’s Hospital CUH, Royal Papworth Hospital, and Cambridge and Peterborough NHS Foundation Trusts 28 days, 90 days, and 180 days after symptom onset. Between August 2020 and July 2021, they recruited 55 Long-COVID patients, all of whom exhibited severe symptoms at least five months after acute COVID-19, who visited the Long-COVID clinic at Addenbrooke’s.

The researchers analyzed blood samples for signs of cytokines, small proteins crucial for the function of immune cells and blood cells. They found that white blood cells in individuals infected with SARS-CoV-2 produced IFN-γ, an inflammation-promoting molecule, which persisted in Long-COVID patients.

Dr. Krishna said, „Interferon Gamma can be used to treat virus infections like Hepatitis C but causes symptoms such as fatigue, fever, headaches, muscle pain, and depression.“ These symptoms are all too familiar to Long-COVID patients. „For us, this was further compelling evidence.“

Using „cell depletion assays,“ the team managed to identify the specific cell types responsible for IFN-γ production. They located immune cells known as CD8+ T cells but noted they required contact with another immune cell type, CD14+ monocytes.

Previous studies have identified IFN-γ signatures with varying approaches and cohorts, but this study’s focus on fatigue revealed a much stronger impact. While previous studies have observed an increase in IFN-γ levels, they did not follow patients long enough to observe when they might decrease again.

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

Vaccination Aids Long-COVID Patients

The team measured IFN-γ release in Long-COVID patients before and after vaccination and observed a significant decrease in IFN-γ post-vaccination in patients whose symptoms resolved.

If SARS-CoV-2 continues to persist in individuals with Long-COVID, triggering an IFN-γ response, vaccination may help eliminate this. However, effective therapies still need to be found,“ said Dr. Krishna.

The number of people with Long-COVID is gradually decreasing, and vaccinations seem to play a crucial role. But new cases are still emerging, and there’s still the big question of what happens when the next coronavirus pandemic arrives. It could lead to another wave of Long-COVID. Understanding what causes Long-COVID now could give us a crucial edge.“


Some highly regarded previous studies have suggested microthrombosis as the main cause of Long-COVID.

Although a role in some form is not ruled out, these new insights suggest that microclots may not be the sole or primary cause.

Classification of Long-COVID

This study argues that the presence of IFN-γ could be used to classify Long-COVID into subtypes that could be used for treatment personalization.

It’s unlikely that all the different Long-COVID symptoms are due to the same cause. We need to differentiate between individuals and tailor treatments on an individual basis. Some patients recover slowly, while others remain trapped in a cycle of fatigue for years. We need to know why,“ said Dr. Krishna.


Journal Reference:

Krishna, BA, et al. (2024) Spontaneous, Persistent, T-cell-dependent IFN-γ Release in Patients Progressing to Long COVID. Science Advances. doi.org/10.1126/sciadv.adi9379.

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