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PreprintCC BYbioRxiv

IFN-κ directs antiviral immunity in human skin

  • J. M. Johnson
  • L. Payne
  • P. Parameswaran
  • Y. Chen
  • M. K. Sarkar
  • A. M. Coon
  • J. M. Kahlenberg
  • J. E. Gudjonsson
  • K. A. Fitzgerald
  • M. Rashighi
  • M. H. Orzalli1
  1. 1UMASS Chan Medical School
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Abstract

Inducible expression of type I IFNs is a well-established host innate defense mechanism to limit virus infection. 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-{kappa}), a poorly studied type I IFN family member. We find that constitutive IFNK 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-{kappa} 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-{kappa}-dependent gene signature in keratinocytes that is not similarly driven by other type I IFNs. Together, this work establishes constitutive IFN-{kappa} production by keratinocytes as a broadly antiviral tissue autonomous defense mechanism.

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Cite

BibTeXRIS
BibTeX
@misc{johnson2026ifnκ,
  title = {{IFN-κ directs antiviral immunity in human skin}},
  author = {J. M. Johnson and L. Payne and P. Parameswaran and Y. Chen and M. K. Sarkar and A. M. Coon and J. M. Kahlenberg and J. E. Gudjonsson and K. A. Fitzgerald and M. Rashighi and M. H. Orzalli},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.19.752886},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.19.752886v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - IFN-κ directs antiviral immunity in human skin
AU  - J. M. Johnson
AU  - L. Payne
AU  - P. Parameswaran
AU  - Y. Chen
AU  - M. K. Sarkar
AU  - A. M. Coon
AU  - J. M. Kahlenberg
AU  - J. E. Gudjonsson
AU  - K. A. Fitzgerald
AU  - M. Rashighi
AU  - M. H. Orzalli
PY  - 2026
DA  - 2026/09/19
PB  - bioRxiv
DO  - 10.64898/2026.09.19.752886
UR  - https://www.biorxiv.org/content/10.64898/2026.09.19.752886v1
AB  - Inducible expression of type I IFNs is a well-established host innate defense mechanism to limit virus infection. 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-{kappa}), a poorly studied type I IFN family member. We find that constitutive IFNK 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-{kappa} 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-{kappa}-dependent gene signature in keratinocytes that is not similarly driven by other type I IFNs. Together, this work establishes constitutive IFN-{kappa} production by keratinocytes as a broadly antiviral tissue autonomous defense mechanism.
ER  -