Summary: In a rodent model, SARS‑CoV‑2 infection leaves a persistent gene expression signature in the dorsal root ganglia (DRG) that remains after the virus is cleared and resembles molecular patterns seen in other pain conditions, suggesting mechanisms for long COVID–related pain and potential therapeutic targets.
Source: Experimental Biology
New animal research offers insight into how SARS‑CoV‑2 (the virus that causes COVID‑19) can produce lasting sensory changes and chronic pain, and it identifies candidate targets for treatment.
“Many people with long COVID report sensory disturbances, including persistent pain and heightened sensitivity,” said Randal (Alex) Serafini, an MD/PhD candidate at the Icahn School of Medicine at Mount Sinai. “We used RNA sequencing to capture how SARS‑CoV‑2 alters gene expression in the dorsal root ganglia, the cluster of sensory neurons that relay pain and touch signals to the spinal cord and brain.”
Using a Syrian hamster model of intranasal SARS‑CoV‑2 infection designed to mimic human COVID‑19 symptoms, researchers observed that infection induced a gene expression signature in the DRG. That signature persisted after the virus had been cleared and showed similarities with molecular patterns associated with pain from inflammation and nerve injury, suggesting a mechanism for prolonged sensory symptoms in long COVID.
Serafini presented these findings at the American Society for Pharmacology and Experimental Therapeutics session of the Experimental Biology (EB) 2022 meeting.
Behavioral testing in infected hamsters revealed a progressive hypersensitivity to touch: a modest increase in sensitivity early after infection that intensified over time and persisted up to 30 days. To determine whether this response is unique to SARS‑CoV‑2 or common to other respiratory RNA viruses, the team compared these results to animals infected with Influenza A.
In contrast to SARS‑CoV‑2, Influenza A produced a pronounced early hypersensitivity that subsided by four days post‑infection. Gene expression analyses of the DRG indicated that SARS‑CoV‑2 produced more sustained and specific changes in genes involved in neuronal signaling and pain modulation, whereas influenza‑driven changes were more transient.
Four weeks after recovery, hamsters that had experienced influenza infection no longer displayed sensory hypersensitivity, while those previously infected with SARS‑CoV‑2 exhibited worsened sensitivity consistent with chronic pain. Molecular profiling showed that the DRG in recovered SARS‑CoV‑2 animals bore transcriptional similarities to DRG from mice with experimentally induced inflammatory or neuropathic pain.
To better understand the molecular pathways behind these altered sensations, investigators applied bioinformatic analyses to the RNA sequencing data. The analyses predicted downregulation of several known pain modulators and highlighted reduced activity of interleukin enhancer binding factor 3 (ILF3), a protein not previously well studied in pain but known for roles in cancer biology and gene regulation.
This predicted downregulation of ILF3 and other regulators occurred at time points when SARS‑CoV‑2‑infected hamsters exhibited only mild pain behavior despite evidence of systemic inflammation. By contrast, influenza‑infected animals showed severe early hypersensitivity at the same stages, underscoring a distinct temporal and molecular profile for SARS‑CoV‑2–related sensory dysfunction.
Based on these molecular predictions, the team tested whether pharmacologically targeting ILF3 could modify pain. They administered a clinically characterized ILF3 inhibitor—originally developed as an anti‑cancer agent—in a mouse model of localized inflammation and found significant pain relief. While further studies are needed, this result suggests that repurposing ILF3 inhibitors or similar agents could offer a therapeutic strategy for COVID‑related acute and chronic pain.
“Our data point to pain mechanisms that may be specific to SARS‑CoV‑2 infection and that can persist after viral clearance,” said Serafini. “Identifying druggable proteins such as ILF3 is encouraging because several cancer‑targeted compounds already exist; repurposing these agents could shorten the path from discovery to clinical application for patients suffering from long COVID pain.”
The research team is now screening additional existing compounds for repurposing potential while also searching for novel inhibitors that modulate ILF3 activity. Future work will be required to validate safety and efficacy in additional animal models and ultimately in human clinical trials before any new treatments could be recommended for people with long COVID‑related pain.
This study was led by Alex Serafini and Justin Frere, MD/PhD candidates at the Icahn School of Medicine at Mount Sinai. Serafini worked with Venetia Zachariou, PhD, professor of neuroscience at Mount Sinai; Frere is a student of Benjamin tenOever, PhD, professor of microbiology at New York University. The findings increase understanding of how SARS‑CoV‑2 can produce lasting alterations in sensory neurons and point toward molecular targets for managing chronic pain after COVID‑19.
About this pain and COVID-19 research news
Author: Nancy Lamontagne
Source: Experimental Biology
Contact: Nancy Lamontagne – Experimental Biology
Image: The image is in the public domain
Original Research: The findings were presented at Experimental Biology 2022.