TY - JOUR T1 - Cyclophilin Inhibitors Restrict Middle East Respiratory Syndrome Coronavirus <em>Via</em> Interferon λ <em>In Vitro</em> And In Mice JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.01826-2019 SP - 1901826 AU - Lucie Sauerhering AU - Alexandra Kupke AU - Lars Meier AU - Erik Dietzel AU - Judith Hoppe AU - Achim D. Gruber AU - Stefan Gattenloehner AU - Biruta Witte AU - Ludger Fink AU - Nina Hofmann AU - Tobias Zimmermann AU - Alexander Goesmann AU - Andrea Nist AU - Thorsten Stiewe AU - Stephan Becker AU - Susanne Herold AU - Christin Peteranderl Y1 - 2020/01/01 UR - http://erj.ersjournals.com/content/early/2020/06/08/13993003.01826-2019.abstract N2 - Rationale While severe coronavirus infections, including Middle East respiratory syndrome coronavirus (MERS-CoV) cause lung injury with high mortality rates, protective treatment strategies are not approved for clinical use.Objectives We elucidated the molecular mechanisms by which the cyclophilin inhibitors Cyclosporin A (CsA) and Alisporivir (ALV) restrict MERS-CoV to validate their suitability as readily-available therapy in MERS-CoV infection.Methods Calu-3 cells and primary human alveolar epithelial cells (hAEC) were infected with MERS-CoV and treated with CsA or ALV or inhibitors targeting cyclophilin inhibitor-regulated molecules including Calcineurin, NFAT, or MAP kinases. Novel CsA-induced pathways were identified by RNA sequencing and manipulated by gene knockdown or neutralising antibodies. Viral replication was quantified by qRT-PCR and TCID50. Data were validated in a murine MERS-CoV infection model.Results CsA and ALV both reduced MERS-CoV titers and viral RNA replication in Calu-3 and hAEC improving epithelial integrity. While neither Calcineurin nor NFAT inhibition reduced MERS-CoV propagation, blockade of c-Jun N-terminal kinase diminished infectious viral particle release but not RNA accumulation. Importantly, CsA induced interferon regulatory factor 1 (IRF1), a pronounced type-III-interferon (IFNλ) response and expression of antiviral genes. Down-regulation of IRF1 or IFNλ increased MERS-CoV propagation in presence of CsA. Importantly, oral application of CsA reduced MERS-CoV replication in vivo, correlating with elevated lung IFNλ levels and improved outcome.Conclusions We provide evidence that cyclophilin inhibitors efficiently decrease MERS-CoV replication in vitro and in vivo via upregulation of inflammatory, antiviral cell responses, in particular IFNλ. CsA might therefore represent a promising candidate to treat MERS-CoV infection.The cyclophilin inhibitors Cyclosporin A and Alisporivir activate host innate immunity by induction of interferon lambda via activation of IRF1 in human lung epithelial cells and in vivo, resulting in a significant inhibition of MERS-CoV. ER -