CU Anschutz Scientists Discover Why Shingles Pain Can Last After Virus is Gone

Researchers at the University of Colorado Anschutz have discovered that small particles in the blood called exosomes are the likely culprit behind why some people with shingles experience lingering pain long after virus has cleared their body.

The study, published today in Annals of Neurology, investigated the cause of post-herpetic neuralgia (PHN) in patients infected with the varicella zoster virus which causes shingles.

“We can completely stop the infection, yet in some patients the pain does not go away,” said the study’s senior author  Andrew Bubak, PhD, associate professor of neurology at CU Anschutz School of Medicine   who studies the role of exosomes in infectious disease.

Exosomes are microscopic packages released by cells that carry proteins and other molecules throughout the body. The study found that a shingles infection can cause nerve cells to release inflammatory signals and become highly active.

"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."

What the researchers found

The scientists discovered that when nerve cells were infected with the shingles virus in the laboratory, the cells became inflamed and showed signs of stress and irritation.

They then collected exosomes from the blood of people with PHN and exposed healthy nerve cells to them. These exosomes caused many of the same harmful changes seen during viral infection—even though no virus was present.

Specifically, the PHN exosomes:

• Triggered inflammation in nerve cells.
• Reduced the ability of nerves to grow and repair themselves.
• Caused structural changes that may make nerves function abnormally.
• Increased production of molecules associated with chronic pain.
• Did not kill the nerve cells, but appeared to keep them in an unhealthy, dysfunctional state.

An important discovery

The researchers expected to see increases in the usual pain-signaling channels found on nerve cells. Instead, they found those channels were actually reduced.

At the same time, levels of substance P, a chemical messenger involved in pain transmission, increased. This suggests that chronic shingles pain may be driven less by traditional nerve firing and more by ongoing chemical signals that keep the pain system activated.

Why this matters

The findings suggest that PHN may develop because the body fails to fully "turn off" the healing response after shingles. Even after the virus has been cleared, exosomes continue delivering damaging messages that prevent nerves from recovering normally.

The researchers describe this as a "failure-to-resolve" model, where the nervous system becomes stuck in a cycle of inflammation and abnormal nerve remodeling.

Potential impact

Bubak said the findings could lead to new therapies to target these exosomes and relieve the pain.

Typical antiviral therapies like acyclovir and valacyclovir target the replicating virus but do not 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 study said.

At the same time, Bubak said if the exosomes maintain this irritable state within the cell, they could also carry therapeutic agents to the target that block specific proteins and help nerves recover and regrow normally after shingles.

“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.

The study co-authors include: Christy S. Niemeyer, Seth Frietze, Serena W.R. Lewis, Emily C. Artman, Christina Coughlan, Safa I. Vaseemuddin, Arianna Gentile Polese, Maria A. Nagel, Stephen K. Tyring, Fyona Okundia, Anthony J. Saviola, Gary C. Curhan, Sharon G. Curhan, Diego Restrepo and Andrew N. Bubak.

Key points

• Exosomes may drive lingering pain after shingles, even after the virus is gone.
• Exosomes from patients with PHN triggered inflammation and nerve dysfunction in healthy nerve cells.
• The findings support a “failure-to-resolve” model, in which nerves remain stuck in an inflamed, dysfunctional state.
• The study points to new potential treatments that target harmful exosome signals or promote nerve repair.