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Cyclophilin inhibitors restrict Middle East respiratory syndrome coronavirus via interferon-λ in vitro and in mice.
Sauerhering, Lucie; Kupke, Alexandra; Meier, Lars; Dietzel, Erik; Hoppe, Judith; Gruber, Achim D; Gattenloehner, Stefan; Witte, Biruta; Fink, Ludger; Hofmann, Nina; Zimmermann, Tobias; Goesmann, Alexander; Nist, Andrea; Stiewe, Thorsten; Becker, Stephan; Herold, Susanne; Peteranderl, Christin.
  • 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.
  • Becker S; Institute of Molecular Oncology, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL), Marburg, Germany.
  • Herold S; Institute of Virology, Philipps University of Marburg, Member of the German Center for Infection Research (DZIF), TTU Emerging Infections, Marburg, Germany.
  • Peteranderl C; Equal contribution.
Eur Respir J ; 56(5)2020 Nov.
Article in English | MEDLINE | ID: covidwho-648811
Semantic information from SemMedBD (by NLM)
1. Middle East Respiratory Syndrome Coronavirus PROCESS_OF Mus
Subject
Middle East Respiratory Syndrome Coronavirus
Predicate
PROCESS_OF
Object
Mus
2. Lung LOCATION_OF Injury cause
Subject
Lung
Predicate
LOCATION_OF
Object
Injury cause
3. Middle East Respiratory Syndrome Coronavirus LOCATION_OF Cyclophilin A
Subject
Middle East Respiratory Syndrome Coronavirus
Predicate
LOCATION_OF
Object
Cyclophilin A
4. Middle East Respiratory Syndrome Coronavirus LOCATION_OF alisporivir
Subject
Middle East Respiratory Syndrome Coronavirus
Predicate
LOCATION_OF
Object
alisporivir
5. Alveolar Epithelial Cells PART_OF Homo sapiens
Subject
Alveolar Epithelial Cells
Predicate
PART_OF
Object
Homo sapiens
6. cyclosporine TREATS Middle East Respiratory Syndrome Coronavirus
Subject
cyclosporine
Predicate
TREATS
Object
Middle East Respiratory Syndrome Coronavirus
7. alisporivir TREATS Middle East Respiratory Syndrome Coronavirus
Subject
alisporivir
Predicate
TREATS
Object
Middle East Respiratory Syndrome Coronavirus
8. Calcineurin INHIBITS JNK Mitogen-Activated Protein Kinases|JUN
Subject
Calcineurin
Predicate
INHIBITS
Object
JNK Mitogen-Activated Protein Kinases|JUN
9. Interferon Regulatory Factor 1 COEXISTS_WITH cyclosporine
Subject
Interferon Regulatory Factor 1
Predicate
COEXISTS_WITH
Object
cyclosporine
10. Middle East Respiratory Syndrome Coronavirus PROCESS_OF Mus
Subject
Middle East Respiratory Syndrome Coronavirus
Predicate
PROCESS_OF
Object
Mus
11. Lung LOCATION_OF Injury cause
Subject
Lung
Predicate
LOCATION_OF
Object
Injury cause
12. Middle East Respiratory Syndrome Coronavirus LOCATION_OF Cyclophilin A
Subject
Middle East Respiratory Syndrome Coronavirus
Predicate
LOCATION_OF
Object
Cyclophilin A
13. Middle East Respiratory Syndrome Coronavirus LOCATION_OF alisporivir
Subject
Middle East Respiratory Syndrome Coronavirus
Predicate
LOCATION_OF
Object
alisporivir
14. Alveolar Epithelial Cells PART_OF Homo sapiens
Subject
Alveolar Epithelial Cells
Predicate
PART_OF
Object
Homo sapiens
15. cyclosporine TREATS Middle East Respiratory Syndrome Coronavirus
Subject
cyclosporine
Predicate
TREATS
Object
Middle East Respiratory Syndrome Coronavirus
16. alisporivir TREATS Middle East Respiratory Syndrome Coronavirus
Subject
alisporivir
Predicate
TREATS
Object
Middle East Respiratory Syndrome Coronavirus
17. Calcineurin INHIBITS JNK Mitogen-Activated Protein Kinases|JUN
Subject
Calcineurin
Predicate
INHIBITS
Object
JNK Mitogen-Activated Protein Kinases|JUN
18. Interferon Regulatory Factor 1 COEXISTS_WITH cyclosporine
Subject
Interferon Regulatory Factor 1
Predicate
COEXISTS_WITH
Object
cyclosporine
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.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Interferons / Cyclosporine / Coronavirus Infections / Cyclophilins / Middle East Respiratory Syndrome Coronavirus Type of study: Prognostic study Limits: Animals / Humans Language: English Year: 2020 Document Type: Article Affiliation country: 13993003.01826-2019

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Interferons / Cyclosporine / Coronavirus Infections / Cyclophilins / Middle East Respiratory Syndrome Coronavirus Type of study: Prognostic study Limits: Animals / Humans Language: English Year: 2020 Document Type: Article Affiliation country: 13993003.01826-2019