1. Selective Janus kinase inhibition preserves interferon-λ–mediated antiviral responses.
- Author
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Schnepf, Daniel, Crotta, Stefania, Thamamongood, Thiprampai, Stanifer, Megan, Polcik, Laura, Ohnemus, Annette, Vier, Juliane, Jakob, Celia, Llorian, Miriam, Gad, Hans Henrik, Hartmann, Rune, Strobl, Birgit, Kirschnek, Susanne, Boulant, Steeve, Schwemmle, Martin, Wack, Andreas, and Staeheli, Peter
- Abstract
Specific inhibition: Janus kinase (JAK) inhibitors are powerful therapeutics used to treat inflammatory diseases but are also linked to immune suppression and complications associated with viral infections. Schnepf et al. show that selective inhibition of tyrosine kinase 2 (TYK2) can block potentially noxious type I IFN signaling but does not alter IFN-λ signaling, whereas the JAK1/2 inhibitor baricitinib blocks both types of IFN responses. Epithelial cells did not require TYK2 for IFN-λ–driven gene expression or antiviral responses, and TYK2-deficient mice have intact IFN-λ–mediated responses and are protected from influenza A virus infection. These findings indicate that TYK2 inhibition may be a better treatment option for type I interferonopathies. Inflammatory diseases are frequently treated with Janus kinase (JAK) inhibitors to diminish cytokine signaling. These treatments can lead to inadvertent immune suppression and may increase the risk of viral infection. Tyrosine kinase 2 (TYK2) is a JAK family member required for efficient type I interferon (IFN-α/β) signaling. We report here that selective TYK2 inhibition preferentially blocked potentially detrimental type I IFN signaling, whereas IFN-λ–mediated responses were largely preserved. In contrast, the clinically used JAK1/2 inhibitor baricitinib was equally potent in blocking IFN-α/β– or IFN-λ–driven responses. Mechanistically, we showed that epithelial cells did not require TYK2 for IFN-λ–mediated signaling or antiviral protection. TYK2 deficiency diminished IFN-α–induced protection against lethal influenza virus infection in mice but did not impair IFN-λ–mediated antiviral protection. Our findings suggest that selective TYK2 inhibitors used in place of broadly acting JAK1/2 inhibitors may represent a superior treatment option for type I interferonopathies to counteract inflammatory responses while preserving antiviral protection mediated by IFN-λ. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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