The coronavirus pandemic has left sequels in many of the people who were infected with SARS-CoV-2 and who, after overcoming the disease, continue to suffer from health problems, which have been defined as persistent or prolonged COVID. Among the numerous symptoms they present – more than 200 have already been identified – there is also a headache or muscle pain, among others. Now a group of scientists has discovered why the pain may be a long-term sequela of this virus.
The results of the research may also help find therapies to treat the pain associated with COVID-19. “A significant number of people suffering from prolonged COVID experience sensory abnormalities, including various forms of pain,” said Dr. Randal (Alex) Serafini, a candidate at the Icahn School of Medicine at Mount Sinai in New York City. “We used RNA sequencing to get a snapshot of the biochemical changes that SARS-CoV-2 triggers in a pain-transmitting structure called the dorsal root ganglion.”
To carry out the study, the researchers used a hamster model of SARS-CoV-2 infection -by the intranasal route-, in which the symptoms of COVID are similar to those experienced by people, and discovered that the infection left a signature of gene expression in dorsal root ganglia that was maintained even after the virus was eliminated. This signature matched patterns of gene expression that had been observed in pain caused by other conditions.
COVID causes alterations that are maintained over time
“Our findings could potentially lead to new therapies for patients suffering from acute and prolonged COVID, as well as other pain conditions,” says Serafini. “Our study also shows that SARS-CoV-2 causes long-term effects on the body in dramatically new ways, further underscoring why people should try to avoid becoming infected.”
“ILF3 inhibitors could potentially target pain mechanisms that are specific to COVID patients, both acutely and chronically”
The researchers found that hamsters infected with the coronavirus exhibited mild hypersensitivity to touch shortly after infection, which became more severe over time, up to 30 days. They then carried out similar experiments with the influenza A virus to see if other RNA viruses promote similar responses.
They observed that the influenza A virus caused more severe early hypersensitivity than that caused by SARS-CoV-2, but that this disappeared four days after infection. By analyzing patterns of gene expression in dorsal root ganglia, they found that SARS-CoV-2 had caused a more relevant change in the expression levels of genes involved in neuron-specific signaling processes compared to SARS-CoV-2. flu.
Four weeks after the rodents recovered from the viral infection, tests showed that while those infected with the flu no longer showed signs of long-term hypersensitivity, those infected with SARS-CoV-2 did show worsening of the disease. hypersensitivity resulting in chronic pain, and gene expression signatures similar to those observed in the dorsal root ganglia of mice affected by pain induced by inflammation or nerve injury.
Potential therapies to relieve post-COVID pain
Bioinformatic analysis allowed scientists to verify that SARS-CoV-2 reduces the activity of several previously identified pain regulators and a protein called interleukin-enhancing binding factor 3 (ILF3). ILF3 has not yet been studied in the context of pain, but it is a potent regulator of cancer. The researchers gave the animals an anticancer drug that inhibits the activity of ILF3 and found that it was highly 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 potentially target pain mechanisms that are specific to COVID patients, both acutely and chronically,” Serafini said. “Interestingly, we saw some cancer-associated proteins emerge 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 repurpose these drugs, this It would drastically reduce the therapeutic development timeline”.
This research was presented by Serafini at the annual meeting of the American Society for Pharmacology and Experimental Therapeutics during the Experimental Biology (EB) 2022 meeting, held in Philadelphia from April 2-5. The researchers are working to identify other compounds that could be repurposed while keeping an eye out for new compounds that could inhibit ILF3 activity.
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