Identification of the antiviral protein IFN-γ as a potential biomarker for Long COVID

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 patients with Long COVID, IFN-y production persists until symptoms improve, highlighting a potential biomarker and target for therapies.

A University of Cambridge-led study identifies the protein interferon gamma (IFN-γ) as a potential biomarker for long-term fatigue from COVID and highlights an immune mechanism behind the disease that could pave the way for the development of much-needed treatments and provide a jumpstart in the event of a future coronavirus pandemic.

The study, published today in science progress, followed a group of patients with long-term COVID fatigue for more than 2.5 years to understand why some recovered and others did not.

Long-term COVID continues to affect millions of people worldwide and places a significant burden on health services. An estimated 1.9 million people in the UK alone (2.9% of the population) were experiencing self-reported long-term COVID as of March 2023, according to the ONS. Fatigue remains by far the most common and debilitating symptom, and patients are still waiting for an effective treatment.

The study shows that initial infection with SARS-CoV-2 triggers the production of the antiviral protein IFN-γ, which is a normal response from the immune system. For most people, when their infection clears, the symptoms of COVID-19 stop and the production of this protein stops, but the researchers found that high levels of IFN-γ remained in some patients with long-term COVID-19 for up to 31 months.

We found a possible mechanism behind Long COVID, which could represent a biomarker – that is, an indicative signature of the condition. We hope this could help pave the way for developing treatments and give some patients a firm 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, Cambridge, where he began collecting blood samples from patients and began studying their immunology. Sithole soon enlisted the support of Dr Benjamin Krishna and Dr Mark Wills from the University of Cambridge’s Department of Medicine.

“When the clinic started, many people didn’t even believe that 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 completed this study.”

The team studied 111 confirmed COVID patients admitted to Addenbrooke’s Hospital CUH, Royal Papworth Hospital and Cambridge and Peterborough NHS Foundation Trusts at 28 days, 90 days and 180 days after the onset of symptoms. Between August 2020 and July 2021, they recruited 55 patients with long-term COVID-19 – all presenting with severe symptoms at least 5 months after acute COVID-19 – attending the Long COVID Clinic at Addenbrooke’s.

The researchers analyzed blood samples for signs of cytokines, small proteins crucial to the function of immune system cells and blood cells. They found that white blood cells from people infected with SARS-CoV-2 produced IFN-γ, a pro-inflammatory molecule, and that this persisted in patients with long-term COVID.

Dr Krishna said: “Interferon gamma can be used to treat viral infections such as hepatitis C, but it causes symptoms such as fatigue, fever, headache, muscle aches and depression. These symptoms are well known to long-term COVID patients. For us, that was another smoking gun.”

By conducting “cell depletion assays,” the team was able to identify the exact cell types responsible for IFN-γ production. They identified the immune system cells known as CD8+ T cells, but found that they required contact with another type of immune cell: CD14+ monocytes.

Previous studies have identified IFN-γ signatures using different approaches and cohorts, but this study’s focus on fatigue revealed a much stronger influence. Also, while previous studies have observed that IFN-y levels increase, they did not follow patients long enough to notice when they might subside.

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

Vaccination helps long-term COVID patients

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

“If SARS-CoV-2 continues to persist in people with long-term COVID-19, inducing an IFN-γ response, then vaccination may help clear this up. But we need to find effective treatments,,” said Dr. Krishna.

“The number of people with Long COVID is gradually decreasing and vaccination seems to play an important role in this. But new cases are still emerging, and then there’s the big question of what will happen when the next coronavirus pandemic hits. We could be facing another Long COVID wave. Understanding what causes Long COVID now could give us a critical head start.“

Microbiosis

Some well-published previous studies have suggested microthrombosis as a root cause of long-term COVID.

Although a role cannot be ruled out, these new findings suggest that microthrombosis may not be the only or the most important 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 to individualize treatment.

“It is unlikely that all the different symptoms of Long COVID are caused by the same thing. We need to differentiate people and tailor treatments. Some patients recover slowly and there are those who are stuck in a cycle of fatigue for years. We need to know why,,” said Dr. Krishna.