Researchers From Icahn School of Medicine Discover That Pain Conditions In Long COVID Caused By Gene Dysregulation In Dorsal Root Ganglia
: 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 Thailand Medical News
, "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.
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.
The team then performed similar experiments with the Influenza A virus to determine if other RNA viruses promote similar responses.
Interestingly, in contrast to SARS-CoV-2, Influenza A caused an early hypersensitivity that was more severe but faded by four days post-infection.
Detailed analysis of gene expression patterns in the dorsal root ganglia revealed that SARS-CoV-2 caused a more prominent change in expression levels of genes implicated in neuron-specific signaling processes compared to influenza.
Subsequent experiments showed that four weeks after recovering from viral infection, fl
u-infected hamsters had no signs of long-term hypersensitivity while SARS-CoV-2-infected hamsters showed worsened hypersensitivity, reflecting chronic pain.
Importantly, the hamsters that had recovered from SARS-CoV-2 had gene expression signatures similar to those seen in the dorsal root ganglia of mice affected by pain that was induced by inflammation or nerve injury.
In order to dive deeper into the molecular machinery associated with altered sensation in SARS-CoV-2-infected infected hamsters, the stud team applied bioinformatic analyses to the gene expression data they had obtained. The analysis predicted that SARS-CoV-2 downregulates the activity of several previously identified pain regulators and a protein called interleukin enhancer binding factor 3 (ILF3).
It was observed that this downregulation occurs at times when pain behaviors in SARS-CoV-2-infected hamsters were very mild, despite heavy systemic inflammation. In contrast, Influenza A-induced hypersensitivity was severe at these timepoints. ILF3 has not yet been studied in the context of pain but is a potent cancer regulator.
From the study findings, the study team hypothesized that mimicking the acute effects of ILF3 could serve as a new pain treatment strategy.
In order to test this prediction, the study team administered a clinically tested anti-cancer drug that inhibits ILF3 activity.
The study team found that it was indeed very effective at treating pain in a mouse model of localized inflammation.
Dr Serafini added, "We think 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. Interestingly, we saw a few cancer-associated proteins come up as predicted pain targets, 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, it could drastically cut down therapeutic development timeline."
The study team are working to identify other compounds that could be repurposed while also keeping an eye out for novel compounds that might inhibit ILF3 activity.
Thailand Medical News
would further like to add that the phytochemical Amentoflavone is believed to also possess the capability to inhibit ILF3 activity.
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