Exosomes Linked to Nerve Irritation, Dysfunction, and Lingering Pain After Shingles

The results of a study by researchers at the University of Colorado Anschutz suggest that that extracellular vesicles known as exosomes in the blood are the likely culprit behind why some people with shingles experience lingering pain—post-herpetic neuralgia (PHN)—long after the causative varicella zoster virus (VZV) has cleared the body.

Exosomes are microscopic packages released by cells that carry proteins and other molecules throughout the body. The research team found that a shingles infection can cause nerve cells to release inflammatory signals and become highly active. When investigators exposed healthy nerve cells in the lab to exosomes collected from the blood of people with PHN, they found that the exosomes triggered in the nerve cells many of the same harmful changes seen during viral infection, even though no virus was present.

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 study results indicate that chronic shingles pain may not simply be the result of damage caused during the initial infection, the study authors noted. Instead, biological signals carried by exosomes may continue to keep nerve cells in an irritated, dysfunctional state and prevent them from healing. 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. This opens the door to entirely new approaches for predicting, preventing, and treating post-herpetic neuralgia.

The researchers, headed by Andrew Bubak, PhD, associate professor of neurology at CU Anschutz who studies the role of exosomes in infectious disease, reported their findings in Annals of Neurology, in a paper titled, “Circulating Exosomes Drive Persistent Neuronal Dysfunction in Post-Herpetic Neuralgia Patients,” concluding, “These findings establish a failure-to-resolve model in which persistent exosome-mediated signaling sustains maladaptive neuronal remodeling after viral clearance, identifying circulating exosome cargo as previously unreported mechanistic contributors to PHN pathogenesis and potential therapeutic targets.”

Varicella zoster virus can establish lifelong latency in sensory ganglia subsequent to primary infection and reactivate to cause herpes zoster—HZ; shingles—the authors explained. “Whereas most individuals recover from HZ, a substantial subset develop post-herpetic neuralgia (PHN), commonly defined as pain persisting for more than three months after rash …”. However, the mechanisms driving the change from acute viral injury to chronic neuropathic pain aren’t well understood. Bubak said, “We can completely stop the infection, yet in some patients the pain does not go away.”

The team’s prior work had demonstrated that plasma-derived exosomes from individuals with acute zoster infection, while non-infectious, carry prothrombotic and immunoregulatory cargo, and can activate platelets and induce proinflammatory cytokine production in vascular cells, promoting an inflammatory state.

Through their newly reported study the scientists discovered that nerve cells infected with the shingles virus in the laboratory became inflamed and showed signs of stress and irritation. Exposure to PHN patient-derived exosomes triggered inflammation in nerve cells and reduced the ability of nerves to grow and repair themselves. Exosome exposure also caused structural changes that may make nerves function abnormally and led to increased production of molecules associated with chronic pain. The exosomes didn’t kill the nerve cells and rather appeared to keep them in an unhealthy, dysfunctional state.

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. “Collectively, our findings point toward a potential ‘failure-to- resolve’ model in which PHN arises not from a fundamentally distinct biological process, but from the persistence and amplification of an initially adaptive, exosome-driven neuronal response,” the authors noted. Bubak said the findings could lead to new therapies to target these exosomes and relieve the pain.

Typical antiviral therapies such as acyclovir and valacyclovir target the replicating virus but do not consistently prevent PHN, “… reinforcing the notion that mechanisms independent of ongoing viral replication sustain the pathological state,” the team continued. “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.”

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. “If exosome cargo contributes to the maintenance of the irritable nociceptor state, then circulating exosomes may represent both a source of therapeutic targets and a minimally invasive biomarker platform,” the authors also noted. “Early exosome profiles during acute HZ could potentially identify individuals at risk of developing PHN, enabling stratification and targeted intervention prior to the establishment of chronic symptoms.”

Bubak added: “This is an important discovery, one that offers hope to those who continue to struggle with often intense pain following infection with shingles.”

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