Interferon Gamma Persistence Provides Insights into Long COVID and Therapeutic Potential

SARS-CoV-2 triggers the production of IFN-γ, an antiviral protein associated with symptoms such as fatigue, muscle ache, and depression. New research indicates that in Long COVID patients, IFN-γ production continues until their symptoms improve, suggesting it could be a biomarker for the condition.

A study led by the University of Cambridge identifies interferon gamma (IFN-γ) as a potential biomarker for Long COVID-related fatigue and highlights an immunological mechanism underlying this disease. This discovery may pave the way for developing needed therapies and provide insights in case of future coronavirus pandemics.

The research, published today in Science Advances, followed 111 patients with confirmed SARS-CoV-2 infections across multiple hospitals over a period exceeding two years to understand why some recovered while others did not. Long COVID affects millions globally and places significant strain on healthcare systems.

An estimated 1.9 million people in the UK alone (2.9% of the population) were experiencing self-reported Long COVID as of March 2023, according to official statistics from ONS. Fatigue remains the most common and debilitating symptom among patients awaiting effective treatment options.

The study reveals that upon initial infection with SARS-CoV-2, production of IFN-γ occurs—a normal immune response. In most individuals, when their infection clears, COVID symptoms subside along with this protein’s production. However, researchers found high levels of IFN-γ persisted in some Long COVID patients for up to 31 months.

“We’ve identified a potential mechanism underlying Long COVID that could serve as a biomarker—a telltale signature of the condition,” said Dr. Benjamin Krishna from the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID). “This finding holds promise for developing therapies and providing definitive diagnoses to some patients.”

The research began in 2020 when Dr. Nyarie Sithole established a Long COVID clinic at Addenbrooke’s Hospital, where he collected blood samples from patients and initiated immunological studies with support from Drs. Benjamin Krishna and Mark Wills from the University of Cambridge’s Department of Medicine.

“When we first set up the clinic, many doubted if Long COVID was real,” said Dr. Sithole. “We owe a huge debt to all our patient volunteers without whom this study would not have been possible.”

The team monitored 111 patients from Addenbrooke’s Hospital CUH, Royal Papworth Hospital, and Cambridge & Peterborough NHS Foundation Trusts at various stages after symptom onset. From August 2020 to July 2021, they recruited 55 Long COVID patients experiencing severe symptoms for at least five months post-infection.

Through blood sample analysis focusing on cytokines—crucial immune system proteins—they found that white blood cells of SARS-CoV-2-infected individuals produced IFN-γ. This protein persisted in those with Long COVID. “Interferon gamma, used to treat viral infections like hepatitis C, causes symptoms such as fatigue and muscle aches familiar to Long COVID patients,” Dr. Krishna noted.

Using ‘cell depletion assays,’ they identified CD8+ T cells responsible for producing IFN-γ but required contact with another immune cell type: CD14+ monocytes/macrophages. Prior studies proposed microclotting as the main cause of Long COVID, which this new research suggests is unlikely to be solely or predominantly responsible.

This study proposes that classifying Long COVID based on IFN-γ presence could lead to personalized treatment strategies. “It’s improbable that all Long COVID symptoms stem from a single cause,” Dr. Krishna explained. “We need to differentiate between patients and tailor treatments accordingly.”