Varicella zoster virus, the neurotropic herpesvirus behind chickenpox and shingles, has long been known to hide silently in sensory neurons after an initial infection, only to reawaken years later with sometimes devastating consequences for the nervous system. What has remained murky is how the brain’s own resident immune cells respond to this virus, and whether they help or harm the nervous system during infection. Now, a team of researchers led by Ok Sarah Shin at Korea University College of Medicine has provided the first direct evidence that human microglia—the brain’s resident macrophages—are not only susceptible to VZV infection but are actively hijacked by the virus in a way that amplifies neuroinflammation and may drive neuropathic pain. The study, published in the Journal of Biomedical Science, identifies a surprising molecular culprit: a scavenger receptor called MARCO that the virus exploits both to enter microglia and to ignite inflammatory signaling.
The research team set out to address a persistent gap in the VZV literature. While numerous studies have characterized how VZV infects neurons, neural stem cells, and astrocytes, the role of microglia—the central innate immune defenders of the brain—had never been systematically examined. Because VZV lacks a suitable animal model, the investigators turned to in vitro systems, comparing the behavior of wild-type VZV strain YC01, isolated from a shingles patient, with the live-attenuated vaccine strain MAV/06 across multiple cellular platforms. These included the HMC3 and HIM human microglial cell lines, the monocytic THP1 line, and, critically, human embryonic stem cell-derived microglia (ESC-MG), a model that closely mimics authentic brain microglia in surface markers and gene expression.
The first surprise came from replication assays. Using quantitative PCR to track viral gene expression—measuring immediate-early genes ORF4 and ORF63 and the early gene ORF54—the researchers found that both microglial cell lines supported VZV gene expression and protein production, with the wild-type strain replicating somewhat more efficiently than the vaccine strain. Immunoblotting and confocal microscopy confirmed that viral glycoprotein E, the most abundant protein of VZV, accumulated in infected cells in a time-dependent manner. Notably, cell viability remained largely intact during the early stages of infection, suggesting that the virus was establishing itself in microglia without immediately killing its host cells. Flow cytometry revealed that YC01-infected microglia markedly upregulated CD45 and CD68, markers of microglial activation and phagocytic activity, and showed enhanced uptake of latex beads and apoptotic cells—signs of a functionally activated, yet potentially exploited, immune cell.
To understand the molecular consequences of infection at scale, the team performed bulk RNA sequencing of infected cells. The results were striking: YC01 infection produced a distinct transcriptional signature characterized by robust induction of antiviral innate immunity genes, including retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated protein 5 (MDA5), IFN-stimulated gene 15 (ISG15), IP-10, and 2′-5′-oligoadenylate synthetase 1 (OAS1). In contrast, the attenuated MAV strain elicited gene expression profiles nearly indistinguishable from mock-infected controls. In the ESC-MG model, this divergence was even more pronounced. Wild-type VZV triggered not only inflammatory and antiviral programs but also a shift toward a disease-associated microglia phenotype, with upregulation of genes such as APOE, TYROBP, and TMEM119 that have been linked to dysfunctional microglia in neurodegenerative contexts. Morphologically, YC01-infected ESC-MG underwent dramatic changes—soma enlargement and a shift toward an amoeboid shape, with three-dimensional analysis revealing increased surface area but reduced filament length, hallmarks of activated microglia—while MAV-infected cells maintained their homeostatic branching.
The inflammatory consequences were equally dramatic. YC01-infected microglia secreted elevated levels of proinflammatory cytokines and chemokines, including IL-6, IL-8, IP-10, and MCP-1/2, as confirmed by ELISA, Luminex multiplex assays, and cytokine antibody arrays. Intriguingly, the team traced part of this inflammatory drive to ORF62, the immediate-early 62 protein of VZV. Twelve of the twenty-four non-synonymous mutations that distinguish the vaccine strain from wild-type virus reside in ORF62. When the researchers expressed wild-type or mutant ORF62 in microglia, the wild-type version drove substantially higher NF-κB and IP-10 promoter activity, fuller nuclear translocation of the p65 subunit of NF-κB, and greater secretion of IL-6, IL-8, IL-1β, and TNF-α upon stimulation. This suggests that mutations acquired during vaccine attenuation dampen the virus’s capacity to provoke inflammation in microglia, providing a mechanistic window into why wild-type and vaccine strains behave so differently in the brain’s immune compartment.
Perhaps the most consequential discovery involved MARCO, the macrophage receptor with collagenous structure. This class A scavenger receptor, traditionally known for bacterial defense, emerged as one of the most highly upregulated genes—more than sixfold—in YC01-infected ESC-MG. Recognizing that other viruses, including herpes simplex virus 1, vaccinia virus, and adenovirus, exploit MARCO for entry, the team hypothesized a similar role for VZV. A series of elegant binding experiments confirmed the suspicion: purified recombinant MARCO bound to VZV glycoprotein E in a dose-dependent manner in an ELISA-based assay, while showing no interaction with glycoprotein B. Confocal microscopy of cells co-expressing MARCO and gE revealed strong membrane colocalization, but this was lost when the C-terminal scavenger receptor cysteine-rich (SRCR) domain of MARCO was deleted. Co-immunoprecipitation experiments cemented the finding that the SRCR domain is essential for the MARCO–gE interaction.
Functionally, MARCO proved to be a genuine proviral factor. Overexpression of full-length MARCO in HMC3 cells significantly elevated expression of VZV ORF4, ORF54, and ORF63 following infection, whereas the SRCR-deleted variant failed to provide the same enhancement. Blocking MARCO with a specific antibody, competing it out with the scavenger receptor ligand polyinosinic acid, or knocking it down with siRNA each significantly suppressed viral gene expression; siRNA treatment reduced VZV gE protein levels by roughly seventy percent. CRISPR-Cas9-generated MARCO-knockout HMC3 cells showed markedly reduced early viral gene transcription compared with wild-type controls, and MARCO knockdown in MeWo cells reduced both viral protein expression and infectious titers as measured by plaque assay. Together, these experiments demonstrate that MARCO facilitates VZV uptake, entry, and replication in microglia, positioning it as a key viral exploitation target.
But MARCO’s role did not end at viral entry. Prior work had established that the SRCR domain of MARCO enhances NF-κB activity through interaction with toll-like receptor 2, and that VZV activates inflammatory cytokines in monocytes and macrophages via TLR2. Co-immunoprecipitation confirmed a physical association between full-length MARCO and TLR2, and luciferase reporter assays in HEK293T cells showed that increasing amounts of MARCO co-transfected with TLR2 produced a dose-dependent enhancement of NF-κB promoter activity. Co-expression of MARCO and TLR2 significantly amplified NF-κB activation in response to both VZV gE and TNF-α. In actual microglia, overexpression of MARCO and TLR2 drove higher IL-6 and IL-8 secretion during VZV infection, while MARCO siRNA had the opposite effect. The picture that emerges is one of a two-pronged exploitation: VZV uses MARCO as a receptor to gain entry, and the gE-bound MARCO then cooperates with TLR2 to supercharge inflammatory signaling, converting the brain’s first line of defense into an engine of neuroinflammation.
The final piece of the puzzle addressed what this means for neurons. The researchers differentiated human embryonic stem cells into sensory neurons enriched for nociceptors—the pain-sensing cells of the dorsal root ganglia—and exposed them to conditioned medium from VZV-infected microglia. The results were compelling. Neuroblastoma cells treated with the infected-microglia secretome showed increased propidium iodide uptake, elevated reactive oxygen species production, and Fluoro-Jade C staining consistent with degeneration. In the ESC-derived sensory neurons, the microglial secretome markedly increased expression of Nav1.8, the nociceptor-specific sodium channel encoded by SCN10A, along with calcitonin gene-related peptide, a neuropeptide central to pain signaling. Crucially, calcium imaging with Fluo-4 AM revealed that conditioned medium from VZV-infected microglia triggered robust calcium influx—a readout of nociceptor activation—while medium from MARCO-knockout infected microglia produced only a modest increase. This establishes a plausible mechanistic chain linking microglial MARCO to the neuropathic pain that so often follows shingles, potentially including the chronic, debilitating post-herpetic neuralgia seen in elderly patients.
The findings carry implications that extend well beyond VZV biology. Growing epidemiological evidence, including natural-experiment studies of shingles vaccination, has suggested that vaccination against herpes zoster reduces the risk of dementia, hinting at a role for VZV-induced neuroinflammation in neurodegenerative processes. By demonstrating that VZV-infected microglia adopt a disease-associated phenotype, secrete a potent inflammatory cocktail, and can amplify nociceptor activity in sensory neurons, this study provides a cellular framework for how the virus might contribute to long-term neurological complications. It also highlights MARCO as a druggable node: blocking its interaction with viral gE or its cooperation with TLR2 could, in principle, simultaneously limit viral spread in the brain and dampen the inflammatory cascade that drives pain and neuronal injury. As the authors note, with VZV vaccines still absent from the national immunization programs of many countries and VZV-associated diseases remaining prevalent worldwide, understanding the molecular choreography between this ancient virus and the brain’s immune sentinels has never been more urgent.
Subject of Research: Human microglial response to Varicella zoster virus infection, focusing on MARCO-mediated viral uptake and TLR2-driven neuroinflammation
Subject of Research: Medicine
Article Title: Microglial MARCO facilitates Varicella zoster virus uptake and triggers TLR2-mediated neuroinflammation
Article References: Lim, J.-S., Oh, S.-J., Hur, J.-Y., Oh, S., Ryu, S.-M., Han, R. T., Park, H., Bowdish, D. M. E., & Shin, O. S. (2026). Microglial MARCO facilitates Varicella zoster virus uptake and triggers TLR2-mediated neuroinflammation. Journal of Biomedical Science, 33(1), Article 53. https://doi.org/10.1186/s12929-026-01256-9
Image Credits: AI Generated
DOI: 10.1186/s12929-026-01256-9
Keywords: Varicella zoster virus, MARCO, TLR2, Microglia, Neuroinflammation, Sensory neurons, Scavenger receptor, Glycoprotein E, Neuropathic pain, NF-κB signaling, ESC-derived microglia, Disease-associated microglia
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Kristina Jarvis. (September 11, 2026). Immune receptor MARCO drives shingles virus brain inflammation. Scienmag. https://scienmag.com/immune-receptor-marco-drives-shingles-virus-brain-inflammation/
Kristina Jarvis. “Immune receptor MARCO drives shingles virus brain inflammation.” Scienmag, 11 September 2026, https://scienmag.com/immune-receptor-marco-drives-shingles-virus-brain-inflammation/. Accessed 11 September 2026.
Kristina Jarvis. “Immune receptor MARCO drives shingles virus brain inflammation.” Scienmag. September 11, 2026. https://scienmag.com/immune-receptor-marco-drives-shingles-virus-brain-inflammation/
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Tags: brain inflammation caused by VZVhost-virus interactionsinnate immune response in the brainMARCO scavenger receptorMARCO scavenger receptor in neuroinflammationmicroglia immune response to shinglesmicroglia infectionmicroglia susceptibility to herpesvirusmicroglia susceptibility to VZVmicroglia-virus interactionmolecular pathways of VZV neuroinflammationneuroimmune interactions in shinglesneuroinflammationneurotropic herpesvirusneurotropic herpesvirus and microglial activationrole of innate immunity in VZV brain infectionshingles virus brain inflammationVaricella zoster virusviral hijacking of brain immune cellsviral hijacking of immune cellsvirus-induced neuropathic painVZV reactivation in nervous systemVZV-induced neuropathic pain mechanisms
