JAK inhibitors remove innate immune barriers to allow viral propagation

Ravlo, E.; Ianevski, A.; Skipperstoen, M.; Lysvand, H.; Schjolberg, J.-O.; Vapalahti, O.; Smura, T.; Vauhkonen, H.; Oksenych, V.; Weber, F.; Strand, M.; Evander, M.; Malmring, J.; Afset, J. E.; Bjoras, M.; Kainov, D. E.

doi:10.1101/2025.02.17.638720

bioRxiv · 10.1101/2025.02.17.638720

JAK inhibitors remove innate immune barriers to allow viral propagation

Ravlo, E.·Ianevski, A.·Skipperstoen, M.·Lysvand, H.·Schjolberg, J.-O.·Vapalahti, O.·Smura, T.·Vauhkonen, H.·Oksenych, V.·Weber, F.·Strand, M.·Evander, M.·Malmring, J.·Afset, J. E.·Bjoras, M.·Kainov, D. E.

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Abstract

Janus kinase (JAK) inhibitors are small-molecule therapeutics that reduce inflammation in autoimmune and inflammatory diseases by modulating the JAK-STAT pathway. While effective in alleviating immune-mediated conditions, JAK inhibitors can impair antiviral defences by suppressing interferon (IFN) responses, potentially increasing susceptibility to viral infections. This study investigates the pro-viral mechanism of JAK inhibitors, focusing on baricitinib, across various cell lines, organoids, and viral strains, including a recombinant Rift Valley fever virus, influenza A virus, SARS-CoV-2, and wild type adenovirus. Our findings demonstrate that baricitinib suppresses transcription of IFN-stimulated genes in non-infected cells (ISGs) which is triggered by type I IFNs produced by infected cells, facilitating viral propagation. The pro-viral effects were influenced by viral load, inhibitor concentration, and structural characteristics of the compound. These results underscore the dual effects of JAK inhibitors: reducing inflammation while potentially exacerbating viral infections. Additionally, the findings highlight opportunities to leverage JAK inhibitors for viral research, vaccine production, and drug screening.

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Ravlo, E., Ianevski, A., Skipperstoen, M., Lysvand, H., Schjolberg, J.-O., Vapalahti, O., Smura, T., Vauhkonen, H., Oksenych, V., Weber, F., Strand, M., Evander, M., Malmring, J., Afset, J. E., Bjoras, M., Kainov, D. E.. 2025-02-21. JAK inhibitors remove innate immune barriers to allow viral propagation. https://doi.org/10.1101/2025.02.17.638720

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