IFN-κ directs antiviral immunity in human skin
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.…
Type I IFN induction is a known innate defense strategy to thwart viral infection. However, many viruses have evolved methods to inhibit these cytokine productions to boost replication, dissemination, and host-to-host transmission. The role of additional antiviral defenses in the event of impaired inducible responses remains unclear. This study reveals that human keratinocytes safeguard the skin against viral invasion through persistent production of IFN-kappa (IFN-{kappa}), a type I IFN family member with limited study.
Constitutive IFN-{kappa} expression shields keratinocytes from skin-adapted RNA and DNA viruses, such as vesicular stomatitis virus (VSV) and herpes simplex virus-1 (HSV-1). Utilizing a human skin organoid model, the research demonstrates that IFN-{kappa} generated by keratinocytes instigates an antiviral state in nearby dermal fibroblasts.
Analysis of the type I IFN receptor (IFNAR) signaling route in cultured keratinocytes and skin organoids indicates that separate pathways govern VSV and HSV-1 replication. While the classic JAK-STAT signaling confers defense against VSV, HSV-1 containment occurs via a JAK-STAT-unrelated pathway.
Transcriptomic examination uncovers a unique IFN-{kappa}-driven gene signature in keratinocytes, distinct from the signature triggered by other type I IFNs. In summary, this research establishes that keratinocytes' perpetual IFN-{kappa} production serves as a broad-spectrum, tissue-autonomous defense mechanism against viral invasion.
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