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Peer-reviewedCC BYScience Advances

Human hair–bearing skin organoids reveal cell type–specific susceptibility and innate immune responses to herpes simplex virus 1

  • Emanuel Wyler1
  • Silvia Albertini2
  • Caroline C. Friedel3
  • Artür Manukyan1
  • Annalena Winterfeldt4
  • Nina Bracker4
  • Jiabin Huang4
  • Susanne Krasemann5
  • Izabela Plumbom6,7
  • Janine Altmüller6,7
  • Thomas Conrad6,7
  • Rudolph Reimer8
8 more authors
  • Carola Schneider8
  • Helena Radbruch9
  • Wali Hafezi10
  • Arne Hansen11
  • Adam Grundhoff12,13
  • Markus Landthaler1,14
  • Nicole Fischer2,13
  • Manja Czech-Sioli4
14 affiliations
  1. 1Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology, Berlin, Germany.
  2. 2Institute for Molecular Virology and Tumorvirology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  3. 3Institute for Informatics, Ludwig-Maximilians-Universität München, Munich, Germany.
  4. 4Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  5. 5Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  6. 6Genomics Technology Platform, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
  7. 7Core Facility Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
  8. 8Technology Platform Microscopy and Image Analysis/Electron Microscopy, Leibniz Institute of Virology, Hamburg, Germany.
  9. 9Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  10. 10Institute of Virology/Clinical Virology, University Hospital Muenster, Muenster, Germany.
  11. 11Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  12. 12Department of Viral Genomics, Leibniz Institute of Virology, Hamburg, Germany.
  13. 13German Center for Infection Research, Partner Site Hamburg-Borstel-Lübeck-Riems, Hamburg, Germany.
  14. 14Institut für Biologie, Humboldt-Universität zu Berlin, Berlin, Germany.
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Abstract

Epithelial surfaces are the primary sites of lytic herpes simplex virus 1 (HSV-1) infection following initial exposure or reactivation from latency. To model this complex environment, we used human hair-bearing skin organoids and combined single-cell spatial transcriptomics with imaging to map viral spread and host responses across skin architecture. Our data suggest delayed progression of the HSV-1 life cycle in epidermal keratinocytes and hair follicle cells compared to the dermis. Infection triggered spatially organized host responses, including induction of IER3 in papillary fibroblasts. In basal keratinocytes, IRF3 was up-regulated in both infected and neighboring uninfected cells, consistent with paracrine activation of antiviral signaling. Inflammatory responses were compartmentalized in a cell type-specific manner, with TNFSF9 (4-1BBL) induced in papillary fibroblasts and tumor necrosis factor-α (TNF-α) induced in keratinocytes. Enzyme-linked immunosorbent assays confirmed secretion of these cytokines and the TNF-α-responsive chemokines CXCL2 and CXCL10. CXCL2 expression was enriched in cells adjacent to TNF-α-expressing cells, highlighting spatial coordination of inflammatory signaling. While interferon-β reduced viral replication, TNF-α and 4-1BBL did not, suggesting that their primary role is to orchestrate immune cell recruitment and activation. These findings establish human hair-bearing skin organoids as a physiologically relevant model for investigating spatial host-HSV-1 interactions.

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Cite

BibTeXRIS
BibTeX
@article{wyler2026human,
  title = {{Human hair–bearing skin organoids reveal cell type–specific susceptibility and innate immune responses to herpes simplex virus 1}},
  author = {Emanuel Wyler and Silvia Albertini and Caroline C. Friedel and Artür Manukyan and Annalena Winterfeldt and Nina Bracker and Jiabin Huang and Susanne Krasemann and Izabela Plumbom and Janine Altmüller and Thomas Conrad and Rudolph Reimer and Carola Schneider and Helena Radbruch and Wali Hafezi and Arne Hansen and Adam Grundhoff and Markus Landthaler and Nicole Fischer and Manja Czech-Sioli},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aef5563},
  url = {https://www.science.org/doi/abs/10.1126/sciadv.aef5563},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Human hair–bearing skin organoids reveal cell type–specific susceptibility and innate immune responses to herpes simplex virus 1
AU  - Emanuel Wyler
AU  - Silvia Albertini
AU  - Caroline C. Friedel
AU  - Artür Manukyan
AU  - Annalena Winterfeldt
AU  - Nina Bracker
AU  - Jiabin Huang
AU  - Susanne Krasemann
AU  - Izabela Plumbom
AU  - Janine Altmüller
AU  - Thomas Conrad
AU  - Rudolph Reimer
AU  - Carola Schneider
AU  - Helena Radbruch
AU  - Wali Hafezi
AU  - Arne Hansen
AU  - Adam Grundhoff
AU  - Markus Landthaler
AU  - Nicole Fischer
AU  - Manja Czech-Sioli
PY  - 2026
DA  - 2026/10/30
JO  - Science Advances
DO  - 10.1126/sciadv.aef5563
UR  - https://www.science.org/doi/abs/10.1126/sciadv.aef5563
AB  - Epithelial surfaces are the primary sites of lytic herpes simplex virus 1 (HSV-1) infection following initial exposure or reactivation from latency. To model this complex environment, we used human hair-bearing skin organoids and combined single-cell spatial transcriptomics with imaging to map viral spread and host responses across skin architecture. Our data suggest delayed progression of the HSV-1 life cycle in epidermal keratinocytes and hair follicle cells compared to the dermis. Infection triggered spatially organized host responses, including induction of IER3 in papillary fibroblasts. In basal keratinocytes, IRF3 was up-regulated in both infected and neighboring uninfected cells, consistent with paracrine activation of antiviral signaling. Inflammatory responses were compartmentalized in a cell type-specific manner, with TNFSF9 (4-1BBL) induced in papillary fibroblasts and tumor necrosis factor-α (TNF-α) induced in keratinocytes. Enzyme-linked immunosorbent assays confirmed secretion of these cytokines and the TNF-α-responsive chemokines CXCL2 and CXCL10. CXCL2 expression was enriched in cells adjacent to TNF-α-expressing cells, highlighting spatial coordination of inflammatory signaling. While interferon-β reduced viral replication, TNF-α and 4-1BBL did not, suggesting that their primary role is to orchestrate immune cell recruitment and activation. These findings establish human hair-bearing skin organoids as a physiologically relevant model for investigating spatial host-HSV-1 interactions.
SN  - 2375-2548
ER  -