Epithelial interferon-γ responsiveness shapes chemokine induction and clinical outcomes in herpes simplex virus infection
4 affiliations
- 1Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington, United States of America
- 2Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America
- 3Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America
- 4Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America
Abstract
Herpes simplex virus type 2 (HSV-2) infects genital epithelia and causes a wide spectrum of clinical outcomes, ranging from asymptomatic viral shedding to recurrent self-limited genital lesions. Interferon gamma (IFNγ) is critical in tissue-resident T-cell mediated antiviral defense against HSV-2 reactivation. However, the responsiveness of epithelial cells to IFNγ and its contribution to disease variability remains poorly understood. Here we investigated IFNγ-mediated antiviral responses in primary keratinocytes and donor-matched fibroblasts from individuals with either asymptomatic or ulcerative HSV-2 infection. Our results revealed that keratinocytes are remarkably sensitive to IFNγ, with altered gene expression observed at doses much lower than previously reported. Keratinocytes exhibited greater sensitivity to IFNγ stimulation than fibroblasts, including robust induction of chemokines involved in immune cell recruitment. Among them, CXCL10 was the most sensitive and strongly induced gene, displaying rapid upregulation even at low IFNγ concentrations. Notably, keratinocytes from individuals with asymptomatic HSV-2 infection exhibited significantly greater IFNγ responses at both the mRNA and protein levels compared with those from symptomatic donors, particularly at physiologically low IFNγ doses. This heightened responsiveness was associated with increased nuclear localization of phosphorylated STAT1 following IFNγ stimulation, despite similar baseline expression of IFNγ receptor and STAT1 across donor groups. While IFNγ pretreatment similarly inhibited HSV replication in keratinocytes from both cohorts, the enhanced chemokine production by keratinocytes from asymptomatic individuals may promote more efficient recruitment of antiviral immune cells. Together, these findings identify intrinsic variation in epithelial IFNγ signaling as a potential host factor associated with clinical outcomes in HSV infection. The results suggest that CXCL10-mediated immune recruitment might be a key mechanism linking tissue-resident T cell cytokine signaling to epithelial antiviral defense. Understanding variability in epithelial barrier immune defense may be crucial to improving therapies and vaccine strategies for genital herpes infection. Author summary: Genital herpes caused by herpes simplex virus type 2 (HSV-2) affects millions worldwide, yet some individuals experience frequent painful outbreaks while others remain symptom-free. We investigated whether skin epidermal keratinocytes, the primary cell type involved in HSV-2 infection initiation, respond differently to immune signals in people with asymptomatic versus recurrent ulcerative genital herpes. We revealed that keratinocytes from individuals with asymptomatic infection were more sensitive to interferon gamma (IFNγ), a key antiviral molecule, and produced higher levels of CXCL10, a crucial protein for recruiting protective immune cells. In contrast, keratinocytes from individuals with ulcerative disease demonstrated weaker responses to IFNγ signaling. These findings suggest that epithelial sensitivity to IFNγ is an important determinant of genital herpes disease severity and could guide new strategies to improve immune control of HSV-2.
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BibTeX
@article{zimenko2026epithelial,
title = {{Epithelial interferon-γ responsiveness shapes chemokine induction and clinical outcomes in herpes simplex virus infection}},
author = {Angelina Zimenko and Ian Hayman and Youyi Fong and Luke D. Monroe and Margaret G. Mills and Alex Greninger and Christine Johnston and Lawrence Corey and Jia Zhu},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014612},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014612},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Epithelial interferon-γ responsiveness shapes chemokine induction and clinical outcomes in herpes simplex virus infection
AU - Angelina Zimenko
AU - Ian Hayman
AU - Youyi Fong
AU - Luke D. Monroe
AU - Margaret G. Mills
AU - Alex Greninger
AU - Christine Johnston
AU - Lawrence Corey
AU - Jia Zhu
PY - 2026
DA - 2026/09/30
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014612
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014612
AB - Herpes simplex virus type 2 (HSV-2) infects genital epithelia and causes a wide spectrum of clinical outcomes, ranging from asymptomatic viral shedding to recurrent self-limited genital lesions. Interferon gamma (IFNγ) is critical in tissue-resident T-cell mediated antiviral defense against HSV-2 reactivation. However, the responsiveness of epithelial cells to IFNγ and its contribution to disease variability remains poorly understood. Here we investigated IFNγ-mediated antiviral responses in primary keratinocytes and donor-matched fibroblasts from individuals with either asymptomatic or ulcerative HSV-2 infection. Our results revealed that keratinocytes are remarkably sensitive to IFNγ, with altered gene expression observed at doses much lower than previously reported. Keratinocytes exhibited greater sensitivity to IFNγ stimulation than fibroblasts, including robust induction of chemokines involved in immune cell recruitment. Among them, CXCL10 was the most sensitive and strongly induced gene, displaying rapid upregulation even at low IFNγ concentrations. Notably, keratinocytes from individuals with asymptomatic HSV-2 infection exhibited significantly greater IFNγ responses at both the mRNA and protein levels compared with those from symptomatic donors, particularly at physiologically low IFNγ doses. This heightened responsiveness was associated with increased nuclear localization of phosphorylated STAT1 following IFNγ stimulation, despite similar baseline expression of IFNγ receptor and STAT1 across donor groups. While IFNγ pretreatment similarly inhibited HSV replication in keratinocytes from both cohorts, the enhanced chemokine production by keratinocytes from asymptomatic individuals may promote more efficient recruitment of antiviral immune cells. Together, these findings identify intrinsic variation in epithelial IFNγ signaling as a potential host factor associated with clinical outcomes in HSV infection. The results suggest that CXCL10-mediated immune recruitment might be a key mechanism linking tissue-resident T cell cytokine signaling to epithelial antiviral defense. Understanding variability in epithelial barrier immune defense may be crucial to improving therapies and vaccine strategies for genital herpes infection. Author summary: Genital herpes caused by herpes simplex virus type 2 (HSV-2) affects millions worldwide, yet some individuals experience frequent painful outbreaks while others remain symptom-free. We investigated whether skin epidermal keratinocytes, the primary cell type involved in HSV-2 infection initiation, respond differently to immune signals in people with asymptomatic versus recurrent ulcerative genital herpes. We revealed that keratinocytes from individuals with asymptomatic infection were more sensitive to interferon gamma (IFNγ), a key antiviral molecule, and produced higher levels of CXCL10, a crucial protein for recruiting protective immune cells. In contrast, keratinocytes from individuals with ulcerative disease demonstrated weaker responses to IFNγ signaling. These findings suggest that epithelial sensitivity to IFNγ is an important determinant of genital herpes disease severity and could guide new strategies to improve immune control of HSV-2.
SN - 1553-7374
ER -