Cyclophilin inhibitors restrict Middle East respiratory syndrome coronavirus via interferon-λ in vitro and in mice.

Autor:	Sauerhering L; Institute of Virology, Philipps University of Marburg, Member of the German Center for Infection Research (DZIF), TTU Emerging Infections, Marburg, Germany., Kupke A; Institute of Virology, Philipps University of Marburg, Member of the German Center for Infection Research (DZIF), TTU Emerging Infections, Marburg, Germany., Meier L; Institute of Virology, Philipps University of Marburg, Member of the German Center for Infection Research (DZIF), TTU Emerging Infections, Marburg, Germany., Dietzel E; Institute of Virology, Philipps University of Marburg, Member of the German Center for Infection Research (DZIF), TTU Emerging Infections, Marburg, Germany., Hoppe J; Dept of Veterinary Pathology, Free University Berlin, Berlin, Germany., Gruber AD; Dept of Veterinary Pathology, Free University Berlin, Berlin, Germany., Gattenloehner S; Dept of Pathology, University Hospital of Giessen, Giessen, Germany., Witte B; Dept of General and Thoracic Surgery, University Hospital of Giessen, Giessen, Germany., Fink L; Institut für Pathologie und Zytologie, Wetzlar, Germany., Hofmann N; Bioinformatics and System Biology, University of Giessen, Giessen, Germany., Zimmermann T; Bioinformatics and System Biology, University of Giessen, Giessen, Germany., Goesmann A; Bioinformatics and System Biology, University of Giessen, Giessen, Germany., Nist A; Genomics Core Facility, Philipps University of Marburg, Marburg, Germany., Stiewe T; Genomics Core Facility, Philipps University of Marburg, Marburg, Germany.; Institute of Molecular Oncology, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL), Marburg, Germany., Becker S; Institute of Virology, Philipps University of Marburg, Member of the German Center for Infection Research (DZIF), TTU Emerging Infections, Marburg, Germany.; Equal contribution., Herold S; Dept of Internal Medicine II, University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.; Equal contribution., Peteranderl C; Dept of Internal Medicine II, University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.; Equal contribution.
Jazyk:	angličtina
Zdroj:	The European respiratory journal [Eur Respir J] 2020 Nov 26; Vol. 56 (5). Date of Electronic Publication: 2020 Nov 26 (Print Publication: 2020).
DOI:	10.1183/13993003.01826-2019
Abstrakt:	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. Competing Interests: Conflict of interest: L. Sauerhering has nothing to disclose. Conflict of interest: A. Kupke has nothing to disclose. Conflict of interest: L. Meier has nothing to disclose. Conflict of interest: E. Dietzel has nothing to disclose. Conflict of interest: J. Hoppe has nothing to disclose. Conflict of interest: A.D. Gruber has nothing to disclose. Conflict of interest: S. Gattenloehner has nothing to disclose. Conflict of interest: B. Witte has nothing to disclose. Conflict of interest: L. Fink has nothing to disclose. Conflict of interest: N. Hofmann has nothing to disclose. Conflict of interest: T. Zimmermann has nothing to disclose. Conflict of interest: A. Goesmann has nothing to disclose. Conflict of interest: A. Nist has nothing to disclose. Conflict of interest: T. Stiewe has nothing to disclose. Conflict of interest: S. Becker has nothing to disclose. Conflict of interest: S. Herold has nothing to disclose. Conflict of interest: C. Peteranderl has nothing to disclose. (Copyright ©ERS 2020.)
Databáze:	MEDLINE
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