Publikationsdatenbank

Cyclophilin inhibitors restrict Middle East respiratory syndrome coronavirus via interferon λ in vitro and in mice (2020)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Sauerhering, Lucie

Kupke, Alexandra

Meier, Lars

Dietzel, Erik

Hoppe, Judith (WE 12)

Gruber, Achim D. (WE 12)

Gattenloehner, Stefan

Witte, Biruta

Fink, Ludger

Hofmann, Nina

Zimmermann, Tobias

Goesmann, Alexander

Nist, Andrea

Stiewe, Thorsten

Becker, Stephan

Herold, Susanne

Peteranderl, Christin

Quelle

The European respiratory journal

Bandzählung: 56

Heftzählung: 5

Seiten: 1901826

ISSN: 0903-1936

Sprache

Englisch

Verweise

URL (Volltext): https://erj.ersjournals.com/content/56/5/1901826

DOI: 10.1183/13993003.01826-2019

Pubmed: 32616594

Kontakt

Institut für Tierpathologie

Robert-von-Ostertag-Str. 15
14163 Berlin
+49 30 838 62450
pathologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

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.