Circulating Exosomes Drive Persistent Neuronal Dysfunction in Post-Herpetic Neuralgia Patients, 2026, Niemeyer et al

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Circulating Exosomes Drive Persistent Neuronal Dysfunction in Post-Herpetic Neuralgia Patients
Christy S. Niemeyer PhD, Seth Frietze PhD, Serena W.R. Lewis MS, Emily C. Artman BS, Christina Coughlan PhD, Safa I. Vaseemuddin BS, Arianna Gentile Polese BS, Maria A. Nagel MD, Stephen K. Tyring MD, Fyona Okundia MD, Anthony J. Saviola PhD, Gary C. Curhan MD, Sharon G. Curhan MD, Diego Restrepo PhD, Andrew N. Bubak PhD

Abstract​

Objective​

Post-herpetic neuralgia (PHN) is a debilitating chronic pain condition persisting beyond 3 months after herpes zoster (HZ), yet the mechanisms driving the transition from acute viral injury to chronic neuropathic pain remain poorly characterized. We tested whether circulating exosomes are sufficient to drive sensory neuron dysfunction independent of direct varicella zoster virus infection.

Methods​

Human nociceptive neurons were either directly infected with varicella zoster virus or exposed to exosomes isolated from sera of control individuals, patients with acute HZ, or patients with post-herpetic neuralgia. Neuronal responses were assessed by bulk RNA sequencing (RNA-seq), gene set enrichment analysis, multiplex cytokine and matrix metalloproteinase-9 immunoassays, lactate dehydrogenase cytotoxicity assays, live-cell imaging of neurite dynamics, and mass spectrometry-based proteomic profiling of exosome cargo.

Results​

Direct viral infection induced a pro-inflammatory, metabolically active neuronal state with increased interleukin-8 and interleukin-13 secretion and elevated extracellular matrix remodeling pathways. PHN exosomes recapitulated and amplified this phenotype in uninfected neurons, suppressing neurite extension gene networks through predicted inhibition of the RNA-binding protein ELAVL4, functionally impairing neurite outgrowth, and inducing matrix metalloproteinase-9 secretion without cytotoxicity. Proteomic profiling identified complement C3b and HSPA5 enriched on PHN exosomes. Canonical nociceptive ion channels were downregulated whereas substance P was upregulated, indicating a shift toward neuropeptide-mediated signaling.

Interpretation​

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. ANN NEUROL 2026

 
Press release
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.
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Possible confounders include age and sex:
mature human sensory neurons were exposed to sera-derived exosomes from individuals with acute HZ [herpes zoster], diagnosed PHN [post-herpetic neuralgia], and controls, and supernatant collected 36 hours later.
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Overall, patients with PHN were older than both the control and HZ cohorts; age is among the strongest driving risk factors for PHN.3 Patients in the PHN group also contained only one male subject.
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This study has limitations inherent to its design. The PHN cohort was older and more female-skewed than the control and acute HZ groups, and the sample sizes across all groups were modest.
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