{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T12:02:25Z","timestamp":1789387345695,"version":"build-2803163510"},"reference-count":59,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Post\u2010herpetic neuralgia (PHN) is a debilitating chronic pain condition persisting beyond 3\u2009months 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2010herpetic neuralgia. Neuronal responses were assessed by bulk RNA sequencing (RNA\u2010seq), gene set enrichment analysis, multiplex cytokine and matrix metalloproteinase\u20109 immunoassays, lactate dehydrogenase cytotoxicity assays, live\u2010cell imaging of neurite dynamics, and mass spectrometry\u2010based proteomic profiling of exosome cargo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Direct viral infection induced a pro\u2010inflammatory, metabolically active neuronal state with increased interleukin\u20108 and interleukin\u201013 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\u2010binding protein ELAVL4, functionally impairing neurite outgrowth, and inducing matrix metalloproteinase\u20109 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\u2010mediated signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>These findings establish a failure\u2010to\u2010resolve model in which persistent exosome\u2010mediated 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<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78352","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T11:02:47Z","timestamp":1789383767000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Circulating Exosomes Drive Persistent Neuronal Dysfunction in Post\u2010Herpetic Neuralgia Patients"],"prefix":"10.1002","author":[{"given":"Christy S.","family":"Niemeyer","sequence":"first","affiliation":[{"name":"Department of Neurology University of Colorado Anschutz School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth","family":"Frietze","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Health Sciences University of Vermont  Burlington Vermont USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena W.R.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Colorado Anschutz School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily C.","family":"Artman","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Colorado Anschutz School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Coughlan","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Colorado Anschutz School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safa I.","family":"Vaseemuddin","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Colorado Anschutz School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna Gentile","family":"Polese","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Colorado Anschutz School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"Nagel","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Colorado Anschutz School of Medicine  Aurora Colorado USA"},{"name":"Department of Ophthalmology University of Colorado Anschutz School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen K.","family":"Tyring","sequence":"additional","affiliation":[{"name":"Center for Clinical Studies and Department of Dermatology McGovern School of Medicine, University of Texas Health Science Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fyona","family":"Okundia","sequence":"additional","affiliation":[{"name":"Center for Clinical Studies and Department of Dermatology McGovern School of Medicine, University of Texas Health Science Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"Saviola","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics University of Colorado Anschutz School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary C.","family":"Curhan","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Department of Medicine Brigham and Women's Hospital, Boston, Massachusetts, USA; 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