The Pain Conditions In Long COVID Are Caused By Gene Dysregulation In Dorsal Root Ganglia

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Researchers from Icahn School of Medicine at Mount Sinai in New York City in a new study involving animal models have discovered that most pain conditions in Long COVID are caused by the SARS-CoV-2 infection leaving a distinct gene expression signature in the dorsal root ganglia that remained even after the virus cleared.

The Long COVID study findings are yet to be published and will be presented at ongoing American Society for Pharmacology and Experimental Therapeutics annual meeting during the Experimental Biology (EB) 2022 meeting, being held till the 5th of April in Philadelphia. https://www.apsebmeeting.org/eb2022/

The study findings from the new animal study have provided important insights into how the SARS-CoV-2 coronavirus ie the pathogen responsible for the COVID-19 disease can lead to long-term pain. The new findings also point to a potential therapy for COVID-related pain.
 
Lead researcher, Dr Randal (Alex) Serafini, an MD/Ph.D. candidate from the Icahn School of Medicine at Mount Sinai in New York City told “A significant number of individuals suffering from long COVID experience sensory abnormalities, including various forms of pain. Our study team used RNA sequencing to get a snapshot of the biochemical changes SARS-CoV-2 triggers in a pain-transmitting structure called dorsal root ganglia.”

Utilizing animal models involving hamsters with SARS-CoV-2 infection, the stud team found that infection left a gene expression signature in the dorsal root ganglia that remained even after the virus cleared. The signature matched gene expression patterns seen in pain caused by other conditions.
 
Dr Serafini added, “Our findings could potentially lead to new therapies for patients suffering from acute and long COVID, as well as other pain conditions.”
 
He further warned, “Our study also shows that SARS-CoV-2 causes long-term effects on the body in drastically new ways, further underscoring why individuals should try to avoid being infected.”


 The study involved a hamster model of intranasal COVID-19 infection that closely reflects symptoms experienced by humans, and the study team observed that SARS-CoV-2-infected hamsters showed a slight hypersensitivity to touch early after infection, which became more severe over time, up to 30 days.

From the study findings, the study team hypothesized that mimicking the acute effects of ILF3 could serve as a new pain treatment strategy.

Closer to treating long COVID pain
“SARS-CoV-2 induced gene changes in the DRG during active infection might be helping to tone down symptoms like myalgias,” Alex Serafini MS, an M.D./Ph.D. student at the Icahn School of Medicine at Mount Sinai in New York City, co-lead author of the paper, told MNT.

“However, after the animals recover from active infection, the gene signature in the DRG starts to reflect a neuropathic state, like what we would normally see after traumatic nerve injury. Their hypersensitivity gets a lot worse over time, which aligns with these gene signatures,” he added.

As the study is yet to be published, Dr. Pollock said he is limited in what he can say about it. He nevertheless noted that the researchers made an interesting observation.

“In the physiology of a body, ‘disease genes’ and drug therapies are not a nail being hit with a hammer. Genes associated with a disease state are like a thread in a tapestry; one thread might add color and dimension to the scene, pulling out the wrong thread might make it all unravel.”
– John A. Pollock, Ph.D.

“RNA sequencing generates a very large pile of data, so my first inclination is to wonder what else they are seeing aside from ILF3. ILF3 is important, but I believe [it is] a transcriptional/translational regulator; it can influence the expression of potentially many other things,” he noted.

The researchers hope their findings will help develop treatments for pain among those with long COVID.

When asked about potential limitations to the research, Dr. Serafini noted that findings in hamster models might not fully translate over to humans. As their study relies heavily on RNA sequencing, he said they may have also overlooked other changes that contribute to the development of COVID-19, such as changes at the protein level.

Dr. Serafini nevertheless pointed out that the current study is a positive step as it moves away from cellular models.

He added that, as they have already been able to validate ILF3 as a regulator of SARS-CoV-2 pain states, they are confident that other therapeutic opportunities relevant for long COVID exist in their datasets.

The researchers are now working to identify other compounds – both new and pre-existing ones – that may be able to inhibit ILF3 activity.

“It is exciting to see quality research that yet again reinforces the fundamental biological connections between the immune system and the nervous system,” added Dr. Pollock.

“While ILF3 expression appears to be involved in these COVID pain states, it is also regulated in a variety of normal and disease states. Exploring how altering its expression relates to other physiological systems involving the immune system—and potentially other tissue—will be important,” he concluded.

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