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10.1183/13993003.01826-2019 http://scihub22266oqcxt.onion/10.1183/13993003.01826-2019 32616594!7331652!32616594     free     free     free Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Eur+Respir+J 2020 ; 56 (5): ä Nephropedia Template TP {{tp|p=32616594|t=2020. Cyclophilin inhibitors restrict Middle East respiratory syndrome coronavirus via interferon-lambda in vitro and in mice |pdf=|usr=}}{{32616594}} gab.com Text Cyclophilin inhibitors restrict Middle East respiratory syndrome coronavirus via interferon-lambda in vitro and in mice JO: Eur Respir J http://www.kidney.de/pget.php?&tw=1&pmid=32616594 #FOAvip 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 (IFNlambda) response and expression of antiviral genes. Downregulation of IRF1 or IFNlambda increased MERS-CoV propagation in the presence of CsA. Importantly, oral application of CsA reduced MERS-CoV replication in vivo, correlating with elevated lung IFNlambda 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 IFNlambda. CsA might therefore represent a promising candidate for treating MERS-CoV infection. Twit Text FOAVip Cyclophilin inhibitors restrict Middle East respiratory syndrome coronavirus via interferon-lambda in vitro and in mice ????Eur Respir J http://www.kidney.de/pget.php?&tw=1&pmid=32616594 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=32616594 #FOAvip English Wikipedia <ref>{{Cite pmid|32616594}}</ref> Cyclophilin inhibitors restrict Middle East respiratory syndrome coronavirus via interferon-lambda in vitro and in mice #MMPMID32616594 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 Eur Respir J 2020[Nov]; 56 (5): ä PMID32616594show ga 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 (IFNlambda) response and expression of antiviral genes. Downregulation of IRF1 or IFNlambda increased MERS-CoV propagation in the presence of CsA. Importantly, oral application of CsA reduced MERS-CoV replication in vivo, correlating with elevated lung IFNlambda 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 IFNlambda. CsA might therefore represent a promising candidate for treating MERS-CoV infection. |Alveolar Epithelial Cells/drug effects/metabolism/virology[MESH] |Animals[MESH] |Calcineurin Inhibitors/pharmacology[MESH] |Cell Culture Techniques[MESH] |Coronavirus Infections/metabolism/*prevention & control[MESH] |Cyclophilins/*antagonists & inhibitors[MESH] |Cyclosporine/*pharmacology[MESH] |Disease Models, Animal[MESH] |Humans[MESH] |Interferon Lambda[MESH] |Interferon Regulatory Factor-1/drug effects/metabolism[MESH] |Interferons/drug effects/*metabolism[MESH] |Mice[MESH] |Middle East Respiratory Syndrome Coronavirus/*drug effects/physiology[MESH]Cyclophilin inhibitors restrict Middle East respiratory syndrome coron(epmc).pdf DeepDyve Pubget Overpricing