RT Journal Article
SR Electronic
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
FD European Respiratory Society
SP 1901826
DO 10.1183/13993003.01826-2019
A1 Lucie Sauerhering
A1 Alexandra Kupke
A1 Lars Meier
A1 Erik Dietzel
A1 Judith Hoppe
A1 Achim D. Gruber
A1 Stefan Gattenloehner
A1 Biruta Witte
A1 Ludger Fink
A1 Nina Hofmann
A1 Tobias Zimmermann
A1 Alexander Goesmann
A1 Andrea Nist
A1 Thorsten Stiewe
A1 Stephan Becker
A1 Susanne Herold
A1 Christin Peteranderl
YR 2020
UL http://erj.ersjournals.com/content/early/2020/06/08/13993003.01826-2019.abstract
AB 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.