{ "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.", "abstract_shown": true, "affiliations": [ "Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington, United States of America", "Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America", "Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America", "Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America" ], "article_type": "Research Article", "arxiv": null, "author_total": 9, "authors": [ { "affs": [ 0 ], "name": "Angelina Zimenko" }, { "affs": [ 1 ], "name": "Ian Hayman" }, { "affs": [ 2 ], "name": "Youyi Fong" }, { "affs": [ 3 ], "name": "Luke D. Monroe" }, { "name": "Margaret G. Mills" }, { "name": "Alex Greninger" }, { "name": "Christine Johnston" }, { "name": "Lawrence Corey" }, { "name": "Jia Zhu" } ], "bibtex": "https://research.draconitic.com/paper/4jdmshfr91wzy.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014612", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014612", "id": "4jdmshfr91wzy", "issns": [ "1553-7374" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014612", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2713|Herpesvirus Infections and Treatments" ], [ "plos", "/Biology and life sciences/Anatomy/Biological tissue/Connective tissue/Connective tissue cells/Fibroblasts" ], [ "plos", "/Biology and life sciences/Anatomy/Biological tissue/Epithelium/Epithelial cells/Keratinocytes" ], [ "plos", "/Biology and life sciences/Cell biology/Cell motility/Chemotaxis/Chemokines" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Connective tissue cells/Fibroblasts" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Epithelial cells/Keratinocytes" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Herpesviruses/Herpes simplex virus/Herpes simplex virus-2" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Viral replication" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/DNA viruses/Herpesviruses/Herpes simplex virus/Herpes simplex virus-2" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Herpesviruses/Herpes simplex virus/Herpes simplex virus-2" ], [ "plos", "/Medicine and health sciences/Anatomy/Biological tissue/Connective tissue/Connective tissue cells/Fibroblasts" ], [ "plos", "/Medicine and health sciences/Anatomy/Biological tissue/Epithelium/Epithelial cells/Keratinocytes" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Herpesviruses/Herpes simplex virus/Herpes simplex virus-2" ], [ "plos", "/Research and analysis methods/Imaging techniques/Fluorescence imaging" ] ], "openalex": "W7214931246", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014612&type=printable", "pmcid": null, "pmid": null, "published": "2026-09-30", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/4jdmshfr91wzy.ris", "sources": [ { "first_seen": "2026-10-30T12:17:37Z", "native_id": "10.1371/journal.ppat.1014612", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014612" } ], "subjects": [ { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" }, { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" }, { "field": "medicine", "origin": "plos:anatomy", "subfield": "physiology" } ], "title": "Epithelial interferon-γ responsiveness shapes chemokine induction and clinical outcomes in herpes simplex virus infection", "title_text": "Epithelial interferon-γ responsiveness shapes chemokine induction and clinical outcomes in herpes simplex virus infection", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:37Z", "url": "https://research.draconitic.com/paper/4jdmshfr91wzy", "venue": "PLOS Pathogens", "versions": [] }