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Yet, many viruses have evolved strategies to suppress the induction of these cytokines to enhance replication, spread, and transmission between hosts. Whether additional antiviral mechanisms protect against infection when inducible responses are compromised is not well understood. Here, we demonstrate that human keratinocytes preemptively protect the skin against virus infection through constitutive production of IFN-kappa (IFN-\u03ba), a poorly studied type I IFN family member. We find that constitutive\n                  <jats:italic>IFNK<\/jats:italic>\n                  expression protects keratinocytes against skin tropic RNA and DNA viruses, including vesicular stomatitis virus (VSV) and herpes simplex virus-1 (HSV-1). Using a human skin organoid model, we further demonstrate that keratinocyte-derived IFN-\u03ba establishes an antiviral state in dermal fibroblasts. Genetic and chemical analysis of the type I IFN receptor (IFNAR) signaling pathway in monocultured keratinocytes and skin organoids revealed that distinct pathways control VSV and HSV-1 replication. While canonical JAK-STAT signaling provided protection against VSV, HSV-1 infection was controlled through a JAK-STAT-independent mechanism. Using transcriptomic analysis, we further identified an IFN-\u03ba-dependent gene signature in keratinocytes that is not similarly driven by other type I IFNs. Together, this work establishes constitutive IFN-\u03ba production by keratinocytes as a broadly antiviral tissue autonomous defense mechanism.\n                <\/jats:p>","DOI":"10.64898\/2026.09.19.752886","type":"posted-content","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T01:05:21Z","timestamp":1790211921000},"source":"Crossref","is-referenced-by-count":0,"title":["IFN-\u03ba directs antiviral immunity in human skin"],"prefix":"10.64898","author":[{"given":"Jafira M.","family":"Johnson","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA"},{"name":"Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurellee","family":"Payne","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA"},{"name":"Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pooja","family":"Parameswaran","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA"},{"name":"Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongzhi","family":"Chen","sequence":"additional","affiliation":[{"name":"Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, MA"},{"name":"Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mrinal K.","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony M.","family":"Coon","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Michelle","family":"Kahlenberg","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Michigan, Ann Arbor, MI"},{"name":"Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johann E.","family":"Gudjonsson","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A.","family":"Fitzgerald","sequence":"additional","affiliation":[{"name":"Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, MA"},{"name":"Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehdi","family":"Rashighi","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan H.","family":"Orzalli","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA"},{"name":"Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092607200869000_2026.09.19.752886v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.06.044"},{"key":"2026092607200869000_2026.09.19.752886v1.2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.606456"},{"key":"2026092607200869000_2026.09.19.752886v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/nri3787"},{"key":"2026092607200869000_2026.09.19.752886v1.4","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1146\/annurev-virology-092818-015756","article-title":"Interferon-Stimulated Genes: What Do They All Do?","volume":"6","year":"2019","journal-title":"Annu Rev Virol"},{"key":"2026092607200869000_2026.09.19.752886v1.5","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.02627"},{"key":"2026092607200869000_2026.09.19.752886v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2017.07.012"},{"key":"2026092607200869000_2026.09.19.752886v1.7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00498"},{"key":"2026092607200869000_2026.09.19.752886v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35209-1"},{"key":"2026092607200869000_2026.09.19.752886v1.9","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M102502200"},{"key":"2026092607200869000_2026.09.19.752886v1.10","doi-asserted-by":"crossref","unstructured":"M. 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