{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:51:13Z","timestamp":1791312673629,"version":"4.3.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014612","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000}}],"reference-count":77,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI007140"],"award-info":[{"award-number":["AI007140"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI184778"],"award-info":[{"award-number":["AI184778"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI143773"],"award-info":[{"award-number":["AI143773"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>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 (IFN\u03b3) is critical in tissue-resident T-cell mediated antiviral defense against HSV-2 reactivation. However, the responsiveness of epithelial cells to IFN\u03b3 and its contribution to disease variability remains poorly understood. Here we investigated IFN\u03b3-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 IFN\u03b3, with altered gene expression observed at doses much lower than previously reported. Keratinocytes exhibited greater sensitivity to IFN\u03b3 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 IFN\u03b3 concentrations. Notably, keratinocytes from individuals with asymptomatic HSV-2 infection exhibited significantly greater IFN\u03b3 responses at both the mRNA and protein levels compared with those from symptomatic donors, particularly at physiologically low IFN\u03b3 doses. This heightened responsiveness was associated with increased nuclear localization of phosphorylated STAT1 following IFN\u03b3 stimulation, despite similar baseline expression of IFN\u03b3 receptor and STAT1 across donor groups. While IFN\u03b3 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 IFN\u03b3 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.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014612","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:44:36Z","timestamp":1790790276000},"page":"e1014612","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epithelial interferon-\u03b3 responsiveness shapes chemokine induction and clinical outcomes in herpes simplex virus infection"],"prefix":"10.1371","volume":"22","author":[{"given":"Angelina","family":"Zimenko","sequence":"first","affiliation":[{"name":"University of Washington School of Medicine","place":["Seattle, Washington, United States of America"],"department":["Department of Laboratory Medicine and Pathology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7712-2872","authenticated-orcid":true,"given":"Ian","family":"Hayman","sequence":"additional","affiliation":[{"name":"University of Washington School of Medicine","place":["Seattle, Washington, United States of America"],"department":["Department of Laboratory Medicine and Pathology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youyi","family":"Fong","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Center","place":["Seattle, Washington, United States of America"],"department":["Vaccine and Infectious Disease Division"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke D.","family":"Monroe","sequence":"additional","affiliation":[{"name":"University of Washington School of Medicine","place":["Seattle, Washington, United States of America"],"department":["Department of Laboratory Medicine and Pathology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0493-9408","authenticated-orcid":true,"given":"Margaret G.","family":"Mills","sequence":"additional","affiliation":[{"name":"University of Washington School of Medicine","place":["Seattle, Washington, United States of America"],"department":["Department of Laboratory Medicine and Pathology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Greninger","sequence":"additional","affiliation":[{"name":"University of Washington School of Medicine","place":["Seattle, Washington, United States of America"],"department":["Department of Laboratory Medicine and Pathology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Johnston","sequence":"additional","affiliation":[{"name":"University of Washington School of Medicine","place":["Seattle, Washington, United States of America"],"department":["Department of Laboratory Medicine and Pathology"]},{"name":"University of Washington School of Medicine","place":["Seattle, Washington, United States of America"],"department":["Department of Medicine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence","family":"Corey","sequence":"additional","affiliation":[{"name":"University of Washington School of Medicine","place":["Seattle, Washington, United States of America"],"department":["Department of Laboratory Medicine and Pathology"]},{"name":"Fred Hutchinson Cancer Center","place":["Seattle, Washington, United States of America"],"department":["Vaccine and Infectious Disease Division"]},{"name":"University of Washington School of Medicine","place":["Seattle, Washington, United States of America"],"department":["Department of Medicine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8676-5105","authenticated-orcid":true,"given":"Jia","family":"Zhu","sequence":"additional","affiliation":[{"name":"University of Washington School of Medicine","place":["Seattle, Washington, United States of America"],"department":["Department of Laboratory Medicine and Pathology"]},{"name":"Fred Hutchinson Cancer Center","place":["Seattle, Washington, United States of America"],"department":["Vaccine and Infectious Disease Division"]},{"name":"Institute of Stem Cell and Regenerative Medicine, University of Washington","place":["Seattle, Washington, United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"issue":"4","key":"ppat.1014612.ref001","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1136\/sextrans-2024-056307","article-title":"Estimated global and regional 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