Scientists discover why prolonged COVID can cause pain

A new animal study provides important information on how COVID-19 disease caused by the SARS-CoV-2 coronavirus can cause long-term pain.

The explanation, according to the study, is that the infection leaves in a pain-transmitting structure a signature of gene expression associated with it and that it remains even after the elimination of the virus. The new findings also point to a possible therapy for COVID-related pain.

“A significant number of people suffering from prolonged COVID experience sensory abnormalities, including various forms of pain. To investigate this, we used RNA sequencing to obtain a snapshot of the biochemical changes that SARS-CoV-2 causes in a pain-transmitting structure called the dorsal root ganglion,” explained Randal Alex Serafini, from the Icahn School of Medicine at Mount Sinai in New York City.

The team used RNA sequencing to obtain a snapshot of the biochemical changes that SARS-CoV-2 triggers in the dorsal root ganglia, which is a pain-transmitting structure. Using a hamster model of SARS-CoV-2 infection, the researchers found that the infection left a gene expression signature in the dorsal root ganglia that remained even after the virus was cleared. The signature matched the patterns of gene expression observed in pain caused by other conditions.

The study also shows that SARS-CoV-2 causes long-term effects on the body “in drastically new ways, further underlining why people should avoid getting infected.” The experiments included a hamster model of intranasal COVID-19 infection, which faithfully reflects the symptoms experienced by people. The researchers observed that hamsters showed a slight hypersensitivity to touch at the beginning of the infection, which worsened over time, up to 30 days.

In contrast to SARS-CoV-2, influenza A caused an early hypersensitivity that was more severe, but disappeared within four days post-infection. Analysis of gene expression patterns in dorsal root ganglia revealed that coronavirus caused a more prominent change in the expression levels of genes involved in neuron-specific signaling processes compared to influenza. Other experiments showed that, four weeks after recovering from viral infection, hamsters infected with influenza had no signs of long-term hypersensitivity, while those with SARS-CoV-2 showed aggravated hypersensitivity, reflecting chronic pain. Animals that had recovered from COVID-19 had gene expression signatures similar to those seen in the dorsal root ganglia of mice affected by inflammation-induced pain or nerve injury.

To deepen the molecular machinery associated with altered sensitivity in hamsters infected with SARS-CoV-2, the researchers applied bioinformatics analysis to the gene expression data they had obtained. The analysis predicted that SARS-CoV-2 lowers the activity of several previously identified pain regulators and of a protein called interleukin enhancer binding factor 3 (ILF3). This down-regulation occurs at times when pain behaviors in hamsters infected with SARS-CoV-2 were very mild, despite strong systemic inflammation. On the other hand, influenza A-induced hypersensitivity was severe at that time.

ILF3 has not yet been studied in the context of pain, but it is a potent regulator of cancer, say the researchers, who hypothesized that mimicking the acute effects of ILF3 could serve as a new pain management strategy. To verify this prediction, they administered a clinically proven anticancer drug that inhibits ILF3 activity and found that it was indeed “very effective” in treating pain in a mouse model of localized inflammation.”

“We believe that therapeutic candidates derived from our gene expression data, such as ILF3 inhibitors, could target pain mechanisms that are specific to patients with both COVID-19 and persistent. Interestingly, we saw that some cancer-associated proteins emerged as intended targets for pain, which is exciting because many drugs have already been developed to act against some of these proteins and have been clinically tested. If we can reuse these drugs, it could dramatically reduce the time for therapeutic development,” said Serafini, who will present the new research at the annual meeting of the American Society for Experimental Pharmacology and Therapeutics during the 2022 Experimental Biology (EB) meeting, which will be held from 2 to 5 April in Philadelphia.

“Our findings could potentially lead to new therapies for patients suffering from acute and prolonged COVID, as well as other pain conditions. Our study also shows that SARS-CoV-2 causes long-term effects on the body in drastically new ways, further underlining why people should try to avoid getting infected,” the expert concluded.

This research was led by Alex Serafini and Justin Frere, MD/PhD candidates from the Icahn School of Medicine in Mount Sinai. Serafini is a student at Venetia Zachariou, PhD, professor of neuroscience at Mount Sinai and Frere is a student of Benjamin TeNoEver, PhD, professor of microbiology at New York University.

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