The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors

Coronaviruses (CoVs) are important human and animal pathogens that induce fatal respiratory, gastrointestinal and neurological disease. The outbreak of the severe acute respiratory syndrome (SARS) in 2002/2003 has demonstrated human vulnerability to (Coronavirus) CoV epidemics. Neither vaccines nor...

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Main Authors: Pfefferle, Susanne (Author) , Schöpf, Julia (Author) , Kögl, Manfred (Author) , Friedel, Caroline Christina (Author) , Müller, Marcel A. (Author) , Carbajo-Lozoya, Javier (Author) , Stellberger, Thorsten (Author) , von Dall'Armi, Ekatarina (Author) , Herzog, Petra (Author) , Kallies, Stefan (Author) , Niemeyer, Daniela (Author) , Ditt, Vanessa (Author) , Kuri, Thomas (Author) , Züst, Roland (Author) , Pumpor, Ksenia (Author) , Hilgenfeld, Rolf (Author) , Schwarz, Frank (Author) , Zimmer, Ralf (Author) , Steffen, Imke (Author) , Weber, Friedemann (Author) , Thiel, Volker (Author) , Herrler, Georg (Author) , Thiel, Heinz-Jürgen (Author) , Schwegmann-Wessels, Christel (Author) , Pöhlmann, Stefan (Author) , Haas, Jürgen (Author) , Drosten, Christian (Author) , von Brunn, Albrecht (Author)
Format: Article (Journal)
Language:English
Published: October 27, 2011
In: PLoS pathogens
Year: 2011, Volume: 7, Issue: 10, Pages: 1-15
ISSN:1553-7374
DOI:10.1371/journal.ppat.1002331
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1371/journal.ppat.1002331
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Author Notes:Susanne Pfefferle, Julia Schöpf, Manfred Kögl, Caroline C. Friedel, Marcel A. Müller, Javier Carbajo-Lozoya, Thorsten Stellberger, Ekatarina von Dall'Armi, Petra Herzog, Stefan Kallies, Daniela Niemeyer, Vanessa Ditt, Thomas Kuri, Roland Züst, Ksenia Pumpor, Rolf Hilgenfeld, Frank Schwarz, Ralf Zimmer, Imke Steffen, Friedemann Weber, Volker Thiel, Georg Herrler, Heinz-Jürgen Thiel, Christel Schwegmann-Wessels, Stefan Pöhlmann, Jürgen Haas, Christian Drosten, Albrecht von Brunn

MARC

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245 1 4 |a The SARS-coronavirus-host interactome  |b identification of cyclophilins as target for pan-coronavirus inhibitors  |c Susanne Pfefferle, Julia Schöpf, Manfred Kögl, Caroline C. Friedel, Marcel A. Müller, Javier Carbajo-Lozoya, Thorsten Stellberger, Ekatarina von Dall'Armi, Petra Herzog, Stefan Kallies, Daniela Niemeyer, Vanessa Ditt, Thomas Kuri, Roland Züst, Ksenia Pumpor, Rolf Hilgenfeld, Frank Schwarz, Ralf Zimmer, Imke Steffen, Friedemann Weber, Volker Thiel, Georg Herrler, Heinz-Jürgen Thiel, Christel Schwegmann-Wessels, Stefan Pöhlmann, Jürgen Haas, Christian Drosten, Albrecht von Brunn 
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520 |a Coronaviruses (CoVs) are important human and animal pathogens that induce fatal respiratory, gastrointestinal and neurological disease. The outbreak of the severe acute respiratory syndrome (SARS) in 2002/2003 has demonstrated human vulnerability to (Coronavirus) CoV epidemics. Neither vaccines nor therapeutics are available against human and animal CoVs. Knowledge of host cell proteins that take part in pivotal virus-host interactions could define broad-spectrum antiviral targets. In this study, we used a systems biology approach employing a genome-wide yeast-two hybrid interaction screen to identify immunopilins (PPIA, PPIB, PPIH, PPIG, FKBP1A, FKBP1B) as interaction partners of the CoV non-structural protein 1 (Nsp1). These molecules modulate the Calcineurin/NFAT pathway that plays an important role in immune cell activation. Overexpression of NSP1 and infection with live SARS-CoV strongly increased signalling through the Calcineurin/NFAT pathway and enhanced the induction of interleukin 2, compatible with late-stage immunopathogenicity and long-term cytokine dysregulation as observed in severe SARS cases. Conversely, inhibition of cyclophilins by cyclosporine A (CspA) blocked the replication of CoVs of all genera, including SARS-CoV, human CoV-229E and -NL-63, feline CoV, as well as avian infectious bronchitis virus. Non-immunosuppressive derivatives of CspA might serve as broad-range CoV inhibitors applicable against emerging CoVs as well as ubiquitous pathogens of humans and livestock. 
650 4 |a Animals 
650 4 |a Antiviral Agents 
650 4 |a Caco-2 Cells 
650 4 |a Chlorocebus aethiops 
650 4 |a Cyclophilins 
650 4 |a Cyclosporine 
650 4 |a HEK293 Cells 
650 4 |a Host-Pathogen Interactions 
650 4 |a Humans 
650 4 |a Jurkat Cells 
650 4 |a Protease Inhibitors 
650 4 |a Protein Interaction Mapping 
650 4 |a SARS Virus 
650 4 |a Severe Acute Respiratory Syndrome 
650 4 |a Two-Hybrid System Techniques 
650 4 |a Vero Cells 
650 4 |a Viral Proteins 
650 4 |a Virus Replication 
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