Journal article

Authors list: Sauerhering, L; Kupke, A; Meier, L; Dietzel, E; Hoppe, J; Gruber, AD; Gattenloehner, S; Witte, B; Fink, L; Hofmann, N; Zimmermann, T; Goesmann, A; Nist, A; Stiewe, T; Becker, S; Herold, S; Peteranderl, C

Publication year: 2020

Pages: 1901826-

Journal: European Respiratory Journal

Volume number: 56

Issue number: 5

Open access status: Hybrid

DOI Link: https://doi.org/10.1183/13993003.01826-2019

Publisher: European Respiratory Society

Abstract: 

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.
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.
Calu-3 cells and primary human alveolar epithelial cells (hAECs) were infected with MERS-CoV and treated with CsA or ALV or inhibitors targeting cyclophilin inhibitor-regulated molecules including calcineurin, nuclear factor of activated T-cells (NFATs) or mitogen-activated protein kinases. Novel CsA-induced pathways were identified by RNA sequencing and manipulated by gene knockdown or neutralising antibodies. Viral replication was quantified by quantitative real-time PCR and 50% tissue culture infective dose. Data were validated in a murine MERS-CoV infection model.
Both CsA and ALV reduced MERS-CoV titres and viral RNA replication in Calu-3 cells and hAECs, 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. Downregulation of IRF1 or IFNλ increased MERS-CoV propagation in the presence of CsA. Importantly, oral application of CsA reduced MERS-CoV replication in vivo, correlating with elevated lung IFNλ levels and improved outcome.
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 for treating MERS-CoV infection.

Harvard Citation style: Sauerhering, L., Kupke, A., Meier, L., Dietzel, E., Hoppe, J., Gruber, A., et al. (2020) Cyclophilin inhibitors restrict Middle East respiratory syndrome coronavirus via interferon-λ in vitro and in mice, European Respiratory Journal, 56(5), p. 1901826. https://doi.org/10.1183/13993003.01826-2019

APA Citation style: Sauerhering, L., Kupke, A., Meier, L., Dietzel, E., Hoppe, J., Gruber, A., Gattenloehner, S., Witte, B., Fink, L., Hofmann, N., Zimmermann, T., Goesmann, A., Nist, A., Stiewe, T., Becker, S., Herold, S., & Peteranderl, C. (2020). Cyclophilin inhibitors restrict Middle East respiratory syndrome coronavirus via interferon-λ in vitro and in mice. European Respiratory Journal. 56(5), 1901826. https://doi.org/10.1183/13993003.01826-2019