Exosomes May Explain Why Shingles Pain Lingers After Infection Clears

Researchers at the University of Colorado Anschutz have found that exosomes may explain why some people with shingles keep feeling pain long after the virus itself is gone. The study, published in Annals of Neurology, examined the biological cause of post-herpetic neuralgia (PHN), a lingering pain condition that can follow infection with the varicella zoster virus, the virus responsible for shingles.

“We can completely stop the infection, yet in some patients the pain does not go away,” said Andrew Bubak, the study’s senior author.

Exosomes are microscopic packages that cells release to carry proteins and other molecules through the body. When the researchers infected nerve cells with the shingles virus in the lab, the cells grew inflamed and showed signs of stress. They then exposed healthy nerve cells to exosomes collected from the blood of people with PHN, and those exosomes reproduced many of the same harmful changes seen during active infection, even though no virus was present, triggering inflammation, limiting the nerves’ ability to grow and repair themselves, and increasing production of molecules linked to chronic pain, all without killing the cells outright.

The team had expected to see more activity in the usual pain-signaling channels on nerve cells, but instead found those channels were reduced. At the same time, levels of substance P, a chemical messenger involved in pain transmission, increased, suggesting chronic shingles pain may be driven less by traditional nerve firing and more by ongoing chemical signals that keep the pain system switched on.

“Our findings suggest that chronic shingles pain may not simply be the result of damage caused during the initial infection,” said the study authors. “Instead, biological signals carried by exosomes may continue to keep nerve cells in an irritated, dysfunctional state and prevent them from healing. This opens the door to entirely new approaches for predicting, preventing, and treating post-herpetic neuralgia.” The researchers describe this as a “failure-to-resolve” model, in which the nervous system gets stuck in a cycle of inflammation and abnormal nerve remodeling even after the virus is gone.

Standard antiviral drugs like acyclovir and valacyclovir target the replicating virus but don’t consistently prevent PHN. “This is consistent with our findings, which suggest that non-infectious circulating exosomes, once generated during acute infection, persist and drive neuronal dysfunction independently of ongoing viral replication,” the researchers said. Bubak said the discovery could lead to new therapies targeting these exosomes directly, which might also be used to deliver agents that help nerves recover. “This is an important discovery, one that offers hope to those who continue to struggle with often intense pain following infection with shingles,” he said.