The researchers found that the immune sensor STING triggers pain in addition to inflammation when viral DNA is activated. The discovery could lead to new treatments for pain during viral infections, including COVID-19, without affecting the immune system. By experimenting with mice infected with the herpes virus, scientists discovered an immune system sensor that detects fragments of the virus and triggers pain-related neurons, independent of inflammation.
A study published in the journal Brain, Behavior and Immunity by researchers from Brazil, the United States and South Korea explores how viral infections cause pain, with the aim of contributing to the development of new pain relief methods.
The article shows that when an immune system sensor called STING (stimulator of interferon genes) recognizes certain nucleic acids, such as viral DNA, a channel known to mediate pain is activated. STING is a key component of the innate immune system and is found in nociceptors (the endings of nerve cells that initiate pain sensation).
The researchers analyzed mice infected with herpes simplex virus 1 (HSV-1), a close relative of the varicella-zoster virus (VZV) that causes chickenpox and shingles. They concluded that removing STING from pain receptors significantly reduced pain without affecting inflammation or viral load.
Scientists believe that the STING signaling pathway is directly related to pain and not inflammation, a finding that may also apply to other viral and bacterial infections, including COVID-19. Recent studies have shown that there is a pain-inducing interaction between SARS-CoV-2 and STING.
Pain is often one of the first symptoms of infection, but its triggering process is poorly understood. Immune cells typically recognize viral nucleic acids, activating receptors and viral signaling, triggering an immune response. These receptors and viral signals are present in pain receptors.
"We show in this article that STING recognizes a part of the virus, probably the DNA, that is involved in the pain-inducing process. At least part of this process seems to be directly related to neuronal activation and not to inflammation. This opens up several prospects," Thiago Mattar Cunha, co-corresponding author of the article, told Agência FAPESP. Cunha is a professor at the Faculty of Medicine, University of São Paulo, Ribeirão Preto (FMRP-USP), Brazil. The other corresponding author is Temugin Berta, associate professor at the University of Cincinnati College of Medicine.
Cunha explained that the team's work is focused on studying the role of this mechanism in protecting subjects from infection in order to develop treatment strategies that avoid pain without affecting the immune system.
"Pain has always been associated with inflammatory processes, but in the past decade, a new concept has emerged in the scientific literature, namely that microorganisms - bacteria and fungi - can activate inflammatory processes through their 'products'. Recent studies have found evidence that viruses can activate pain neurons by expressing certain receptors such as STING. We decided to explore this pathway," said Cunha, who is a member of the Center for Research in Inflammatory Diseases (CRID), a FAPESP-funded Research, Innovation and Dissemination Center (RIDC).
In 2017, Cunha co-authored an article published in the Journal of Neuroscience showing that immune mechanisms triggered by VZV alter the function of sensory neurons when reactivated, leading to herpetic neuralgia.
One of the contributions of CRID's research at that time was the validation of an animal model for studying the molecular mechanisms involved in herpes zoster neuralgia, which was also used in the research described in this latest article. Because VZV does not infect mice, the team used HSV-1, a related microorganism that causes oral and genital skin lesions in humans.
Chickenpox is a highly contagious viral infection that causes an itchy, blister-like rash on the skin and is a classic childhood disease. In most cases, chickenpox is benign, but its causative agent, VZV, remains in the body forever and may be reactivated years later, causing shingles (a disease that often occurs in people with HIV/AIDS).
There are no consistent data on chickenpox incidence in Brazil because only severe cases requiring hospitalization and deaths due to the disease must be notified. However, the Ministry of Health estimates that there are about 3 million new cases every year. An epidemiological analysis conducted in May 2024 found that 25,605 people were hospitalized with VZV infection between 2013 and 2023, 26% of whom were aged 70-79 years.
Traditionally, activation of STING "recruits" the protein TBK1, which induces the production of interferons, molecules necessary for immune responses. However, studies have shown that inhibiting TBK1 reduces pain, while blocking interferon has no effect, suggesting that STING triggers pain through separate and independent pathways.
Research also shows that activating STING activates TRPV1 ion channels, leading to depolarization of nociceptors. This post-transcriptional mechanism is also a new discovery beyond the known mechanisms of STING signal transduction.
Compiled from/SciTechDaily