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Preclinical Research Deciphers the Roots of Chronic Pain in Long COVID

lung neurons infected with SARS-CoV-2 compared to mock infected neurons
Protein expression pattern in thoracic dorsal root ganglia of SARS-CoV-2–infected and control (mock) male hamsters, and lung tissue of infected males. | Serafini et al., Sci. Signal. 16, eade4984 (2023)

Although the world has started to emerge from the ravages of the COVID-19 pandemic, many survivors worldwide continue to deal with a mysterious and painful condition known as long COVID.

Now, new preclinical research in Science Signaling takes some of the first steps toward understanding the roots of chronic pain in long COVID. Persistent pain is one of the condition's most burdensome symptoms and can last for months after infection.

The study, published in the May 9 issue, involved experiments in hamsters infected with the SARS-CoV-2 virus. It revealed that the virus left residual genetic material in touch-sensing neurons, which triggered long-lasting changes that left the rodents sensitive to pain.

By providing some much-needed insight into how the virus disrupts the genetic activity of sensory neurons, the research might inform ongoing efforts to understand other symptoms that afflict COVID "long-haulers," such as changes in smell and taste.

More directly, the findings also include some early results that suggest it's possible to target certain proteins and gene signatures to relieve pain, according to the authors of the paper.

"These unique signatures could serve as future targets," said Benjamin tenOever, a professor of microbiology at Icahn School of Medicine at Mount Sinai in New York City and a senior author of the new research. "The data is now available for other groups to join in efforts to find new therapeutic strategies.

COVID's Lingering Effects on Survivors

As of May 10, 2023, there have been more than 765 million confirmed cases of COVID-19 and more than 6.9 million deaths, according to the World Health Organization's COVID-19 dashboard.

The staggering death count firmly places the COVID-19 pandemic as one of the deadliest in history and is the grimmest and most obvious reminder of the toll that the pandemic has taken on the world.

However, the pandemic has also exacted other costs that have grown more obvious with the passage of time. For example, many survivors of COVID-19 infections have gone on to develop long-term complications and symptoms that have perplexed scientists.

These complications are known as long COVID, an umbrella term that encompasses more than 200 reported symptoms but most commonly includes chronic fatigue, pain, shortness of breath and a persistent "brain fog."

The World Health Organization defines long COVID as the continuation or appearance of new symptoms three months after the initial infection. They also estimate that as many as 10% to 20% of infected people can develop these symptoms.

As a result, health authorities have recognized long COVID as a widespread and growing threat to public health. The WHO cites research suggesting that as many as 17 million people were living with long COVID in Europe in 2021, and other studies suggest that the condition might impact at least 65 million people worldwide.

Despite this recognition, scientists are still unsure about why and how the SARS-CoV-2 virus causes lingering pain and other sensory symptoms in some people and not in others.

"Biologically, few medical conditions we know of involve one pathogen inducing such a wide array of systemic symptoms for such a prolonged period of time," said Randal Serafini, a graduate student at Icahn School of Medicine at Mount Sinai and lead author of the study.

"Several theories are starting to be strengthened, such as microclotting, [RNA debris], and viral reservoirs, but no one has found a causal link yet," he added when discussing the uniqueness of long COVID.

Hamster Studies Offer Clues About Pain in Long-Haulers

Over the past few years, Serafini, tenOever and senior author Venetia Zachariou have led a group of scientists that have sought to define the long-term impact of COVID-19 on survivors.

In a 2022 paper published in Science Translational Medicine, tenOever and Zachariou, a professor of neuroscience at Icahn School of Medicine at Mount Sinai, discovered that infections with SARS-CoV-2 in hamsters inflicted damage on their lungs, kidneys and smell-sensing tissues. This damage lasted long after the initial infection, leading the researchers to theorize that it could be responsible for disruptions in smell commonly reported in patients.

Since then, the team has also investigated the roots of other symptoms in long COVID. In this new study, Serafini, tenOever, Zachariou and other researchers theorized that chronic pain in long COVID might be connected to how the virus interacts with sensory neurons.

These neurons register common sensations that can go awry in long COVID, such as smells, tastes and painful stimuli.

To test their hypothesis, the researchers examined neurons and sensory tissues in Syrian golden hamsters infected with SARS-CoV-2. Hamsters offer a good model to study the disease because they show similar clinical symptoms and biological changes after infection when compared to humans, tenOever said.

The team eventually detected non-infectious viral RNA in dorsal root ganglia, which are clusters of nerve tissues in the spine. This leftover viral "debris" triggered changes in the expression of genes, which persisted after the hamsters had recovered from infection, according to the study.

Even after recovering from infection, the hamsters still showed signs of mild but prolonged pain sensitivity. The team didn't observe similar changes in another group of hamsters that recovered from infections with the flu virus.

"Our findings in this study and a prior Science Translational Medicine study support the idea that RNA debris from the infection results in persistent immune engagement as an underlying cause of long COVID symptoms in the brain, and now the peripheral nervous system," Serafini said.

An Important Step for Pain-Relieving Treatments

Not content with discovering the mechanism, the scientists then studied whether it might be possible to somehow target or reverse these disruptions in neurons to relieve pain.

Applying a combination of sequencing and bioinformatics, Serafini's group identified some potential targets for treatments, including a protein named ILF3. They found that the experimental cancer drug YM155 inhibited ILF3 and relieved pain sensitivity in a mouse model of inflammatory pain.

In another experiment, the researchers compared gene activity between hamsters with long COVID and existing models of chronic pain and identified both overlapping and unique changes in gene activity. They posit that these signatures could also offer alternative treatment targets and have made their data available for other research groups.

When asked about translating their work to humans, Zachariou was cautious and noted that it's tricky to study sensory neurons and tissue in people with long COVID.

"We are definitely interested in better understanding the translational potential of this hamster model in humans, but acquisition of dorsal root ganglia from long COVID patients is very difficult," she noted. "We are always open to starting new collaborations with groups that have this capability."

However, her team is taking the first steps to further test treatments aimed at inhibiting ILF3. They would also like to study whether these treatments could help relieve pain in long COVID and other disorders such as chronic fatigue syndrome.

"This might be a first step to working with the pharmaceutical industry to develop refined inhibitors for human trials, but this is … still in the early stages," Zachariou said.