JAK inhibitors remove innate immune barriers facilitating viral propagation
Erlend Ravlo, Aleksandr Ianevski, Marius Nårstad Skipperstøen, Hilde Lysvand, Jørn-Ove Schjølberg, Ole Solheim, Wei Wang, Miroslava Kiššová, Marthe Vestvik, Olli Vapalahti, Teemu Smura, Hanna Vauhkonen, Valentyn Oksenych, Friedemann Weber, Mårten Strand, Magnus Evander, Janne Fossum Malmring, Jan Egil Afset, Magnar Bjørås, Denis E. Kainov
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, which is triggered by type I IFNs produced by infected cells, facilitating viral propagation. The pro-viral effect was 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.