The SARS-Coronavirus-Host Interactome: Identification of Cyclophilins as Target for Pan-Coronavirus Inhibitors
Identifieur interne : 001405 ( Pmc/Curation ); précédent : 001404; suivant : 001406The SARS-Coronavirus-Host Interactome: Identification of Cyclophilins as Target for Pan-Coronavirus Inhibitors
Auteurs : Susanne Pfefferle [Allemagne] ; Julia Schöpf [Allemagne] ; Manfred Kögl [Allemagne] ; Caroline C. Friedel [Allemagne] ; Marcel A. Müller [Allemagne] ; Javier Carbajo-Lozoya [Allemagne] ; Thorsten Stellberger [Allemagne] ; Ekatarina Von Dall Rmi [Allemagne] ; Petra Herzog [Allemagne] ; Stefan Kallies [Allemagne] ; Daniela Niemeyer [Allemagne] ; Vanessa Ditt [Allemagne] ; Thomas Kuri [Allemagne] ; Roland Züst [Suisse] ; Ksenia Pumpor [Allemagne] ; Rolf Hilgenfeld [Allemagne] ; Frank Schwarz [Allemagne] ; Ralf Zimmer [Allemagne] ; Imke Steffen [Allemagne] ; Friedemann Weber [Allemagne] ; Volker Thiel [Suisse] ; Georg Herrler [Allemagne] ; Heinz-Jürgen Thiel [Allemagne] ; Christel Schwegmann-We Els [Allemagne] ; Stefan Pöhlmann [Allemagne] ; Jürgen Haas [Allemagne, Royaume-Uni] ; Christian Drosten [Allemagne] ; Albrecht Von Brunn [Allemagne]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2011.
Abstract
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.
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DOI: 10.1371/journal.ppat.1002331
PubMed: 22046132
PubMed Central: 3203193
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Freiburg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff11"><addr-line>Institute of Virology, Philipps-Universität Marburg, Marburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, Philipps-Universität Marburg, Marburg</wicri:regionArea></affiliation></author><author><name sortKey="Thiel, Volker" sort="Thiel, Volker" uniqKey="Thiel V" first="Volker" last="Thiel">Volker Thiel</name><affiliation wicri:level="1"><nlm:aff id="aff8"><addr-line>Institute of Immunobiology, Kantonsspital St. Gallen, Switzerland</addr-line></nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Immunobiology, Kantonsspital St. Gallen</wicri:regionArea></affiliation></author><author><name sortKey="Herrler, Georg" sort="Herrler, Georg" uniqKey="Herrler G" first="Georg" last="Herrler">Georg Herrler</name><affiliation wicri:level="1"><nlm:aff id="aff12"><addr-line>Institute of Virology, Tierärztliche Hochschule Hannover, Hannover, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, Tierärztliche Hochschule Hannover, Hannover</wicri:regionArea></affiliation></author><author><name sortKey="Thiel, Heinz Jurgen" sort="Thiel, Heinz Jurgen" uniqKey="Thiel H" first="Heinz-Jürgen" last="Thiel">Heinz-Jürgen Thiel</name><affiliation wicri:level="1"><nlm:aff id="aff13"><addr-line>Institute for Virology, Fachbereich Veterinärmedizin, Justus-Liebig Universität Gießen, Giessen, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute for Virology, Fachbereich Veterinärmedizin, Justus-Liebig Universität Gießen, Giessen</wicri:regionArea></affiliation></author><author><name sortKey="Schwegmann We Els, Christel" sort="Schwegmann We Els, Christel" uniqKey="Schwegmann We Els C" first="Christel" last="Schwegmann-We Els">Christel Schwegmann-We Els</name><affiliation wicri:level="1"><nlm:aff id="aff12"><addr-line>Institute of Virology, Tierärztliche Hochschule Hannover, Hannover, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, Tierärztliche Hochschule Hannover, Hannover</wicri:regionArea></affiliation></author><author><name sortKey="Pohlmann, Stefan" sort="Pohlmann, Stefan" uniqKey="Pohlmann S" first="Stefan" last="Pöhlmann">Stefan Pöhlmann</name><affiliation wicri:level="1"><nlm:aff id="aff10"><addr-line>Institute of Virology, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, Hannover Medical School, Hannover</wicri:regionArea></affiliation></author><author><name sortKey="Haas, Jurgen" sort="Haas, Jurgen" uniqKey="Haas J" first="Jürgen" last="Haas">Jürgen Haas</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University (LMU) Munich, München, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University (LMU) Munich, München</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff14"><addr-line>Division of Pathway Medicine, University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Division of Pathway Medicine, University of Edinburgh, Edinburgh</wicri:regionArea></affiliation></author><author><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Virology, University of Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn, Bonn</wicri:regionArea></affiliation></author><author><name sortKey="Von Brunn, Albrecht" sort="Von Brunn, Albrecht" uniqKey="Von Brunn A" first="Albrecht" last="Von Brunn">Albrecht Von Brunn</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University (LMU) Munich, München, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University (LMU) Munich, München</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22046132</idno><idno type="pmc">3203193</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203193</idno><idno type="RBID">PMC:3203193</idno><idno type="doi">10.1371/journal.ppat.1002331</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">001405</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001405</idno><idno type="wicri:Area/Pmc/Curation">001405</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">001405</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The SARS-Coronavirus-Host Interactome: Identification of Cyclophilins as Target for Pan-Coronavirus Inhibitors</title><author><name sortKey="Pfefferle, Susanne" sort="Pfefferle, Susanne" uniqKey="Pfefferle S" first="Susanne" last="Pfefferle">Susanne Pfefferle</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Bernhard-Nocht-Institute, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Bernhard-Nocht-Institute, Hamburg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Virology, University of Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn, Bonn</wicri:regionArea></affiliation></author><author><name sortKey="Schopf, Julia" sort="Schopf, Julia" uniqKey="Schopf J" first="Julia" last="Schöpf">Julia Schöpf</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University (LMU) Munich, München, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University (LMU) Munich, München</wicri:regionArea></affiliation></author><author><name sortKey="Kogl, Manfred" sort="Kogl, Manfred" uniqKey="Kogl M" first="Manfred" last="Kögl">Manfred Kögl</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>DKFZ, Heidelberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>DKFZ, Heidelberg</wicri:regionArea></affiliation></author><author><name sortKey="Friedel, Caroline C" sort="Friedel, Caroline C" uniqKey="Friedel C" first="Caroline C." last="Friedel">Caroline C. Friedel</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>Institute for Informatics, LMU Munich, München, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute for Informatics, LMU Munich, München</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff6"><addr-line>Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg</wicri:regionArea></affiliation></author><author><name sortKey="Muller, Marcel A" sort="Muller, Marcel A" uniqKey="Muller M" first="Marcel A." last="Müller">Marcel A. Müller</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Virology, University of Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn, Bonn</wicri:regionArea></affiliation></author><author><name sortKey="Carbajo Lozoya, Javier" sort="Carbajo Lozoya, Javier" uniqKey="Carbajo Lozoya J" first="Javier" last="Carbajo-Lozoya">Javier Carbajo-Lozoya</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University (LMU) Munich, München, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University (LMU) Munich, München</wicri:regionArea></affiliation></author><author><name sortKey="Stellberger, Thorsten" sort="Stellberger, Thorsten" uniqKey="Stellberger T" first="Thorsten" last="Stellberger">Thorsten Stellberger</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University (LMU) Munich, München, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University (LMU) Munich, München</wicri:regionArea></affiliation></author><author><name sortKey="Von Dall Rmi, Ekatarina" sort="Von Dall Rmi, Ekatarina" uniqKey="Von Dall Rmi E" first="Ekatarina" last="Von Dall Rmi">Ekatarina Von Dall Rmi</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University (LMU) Munich, München, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University (LMU) Munich, München</wicri:regionArea></affiliation></author><author><name sortKey="Herzog, Petra" sort="Herzog, Petra" uniqKey="Herzog P" first="Petra" last="Herzog">Petra Herzog</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Virology, University of Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn, Bonn</wicri:regionArea></affiliation></author><author><name sortKey="Kallies, Stefan" sort="Kallies, Stefan" uniqKey="Kallies S" first="Stefan" last="Kallies">Stefan Kallies</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Virology, University of Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn, Bonn</wicri:regionArea></affiliation></author><author><name sortKey="Niemeyer, Daniela" sort="Niemeyer, Daniela" uniqKey="Niemeyer D" first="Daniela" last="Niemeyer">Daniela Niemeyer</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Virology, University of Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn, Bonn</wicri:regionArea></affiliation></author><author><name sortKey="Ditt, Vanessa" sort="Ditt, Vanessa" uniqKey="Ditt V" first="Vanessa" last="Ditt">Vanessa Ditt</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Virology, University of Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn, Bonn</wicri:regionArea></affiliation></author><author><name sortKey="Kuri, Thomas" sort="Kuri, Thomas" uniqKey="Kuri T" first="Thomas" last="Kuri">Thomas Kuri</name><affiliation wicri:level="1"><nlm:aff id="aff7"><addr-line>IMMH, Albert-Ludwigs-University-Freiburg, Freiburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>IMMH, Albert-Ludwigs-University-Freiburg, Freiburg</wicri:regionArea></affiliation></author><author><name sortKey="Zust, Roland" sort="Zust, Roland" uniqKey="Zust R" first="Roland" last="Züst">Roland Züst</name><affiliation wicri:level="1"><nlm:aff id="aff8"><addr-line>Institute of Immunobiology, Kantonsspital St. Gallen, Switzerland</addr-line></nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Immunobiology, Kantonsspital St. Gallen</wicri:regionArea></affiliation></author><author><name sortKey="Pumpor, Ksenia" sort="Pumpor, Ksenia" uniqKey="Pumpor K" first="Ksenia" last="Pumpor">Ksenia Pumpor</name><affiliation wicri:level="1"><nlm:aff id="aff9"><addr-line>Institute of Biochemistry, University of Luebeck, Luebeck, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry, University of Luebeck, Luebeck</wicri:regionArea></affiliation></author><author><name sortKey="Hilgenfeld, Rolf" sort="Hilgenfeld, Rolf" uniqKey="Hilgenfeld R" first="Rolf" last="Hilgenfeld">Rolf Hilgenfeld</name><affiliation wicri:level="1"><nlm:aff id="aff9"><addr-line>Institute of Biochemistry, University of Luebeck, Luebeck, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry, University of Luebeck, Luebeck</wicri:regionArea></affiliation></author><author><name sortKey="Schwarz, Frank" sort="Schwarz, Frank" uniqKey="Schwarz F" first="Frank" last="Schwarz">Frank Schwarz</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>DKFZ, Heidelberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>DKFZ, Heidelberg</wicri:regionArea></affiliation></author><author><name sortKey="Zimmer, Ralf" sort="Zimmer, Ralf" uniqKey="Zimmer R" first="Ralf" last="Zimmer">Ralf Zimmer</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>Institute for Informatics, LMU Munich, München, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute for Informatics, LMU Munich, München</wicri:regionArea></affiliation></author><author><name sortKey="Steffen, Imke" sort="Steffen, Imke" uniqKey="Steffen I" first="Imke" last="Steffen">Imke Steffen</name><affiliation wicri:level="1"><nlm:aff id="aff10"><addr-line>Institute of Virology, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, Hannover Medical School, Hannover</wicri:regionArea></affiliation></author><author><name sortKey="Weber, Friedemann" sort="Weber, Friedemann" uniqKey="Weber F" first="Friedemann" last="Weber">Friedemann Weber</name><affiliation wicri:level="1"><nlm:aff id="aff7"><addr-line>IMMH, Albert-Ludwigs-University-Freiburg, Freiburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>IMMH, Albert-Ludwigs-University-Freiburg, Freiburg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff11"><addr-line>Institute of Virology, Philipps-Universität Marburg, Marburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, Philipps-Universität Marburg, Marburg</wicri:regionArea></affiliation></author><author><name sortKey="Thiel, Volker" sort="Thiel, Volker" uniqKey="Thiel V" first="Volker" last="Thiel">Volker Thiel</name><affiliation wicri:level="1"><nlm:aff id="aff8"><addr-line>Institute of Immunobiology, Kantonsspital St. Gallen, Switzerland</addr-line></nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Immunobiology, Kantonsspital St. Gallen</wicri:regionArea></affiliation></author><author><name sortKey="Herrler, Georg" sort="Herrler, Georg" uniqKey="Herrler G" first="Georg" last="Herrler">Georg Herrler</name><affiliation wicri:level="1"><nlm:aff id="aff12"><addr-line>Institute of Virology, Tierärztliche Hochschule Hannover, Hannover, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, Tierärztliche Hochschule Hannover, Hannover</wicri:regionArea></affiliation></author><author><name sortKey="Thiel, Heinz Jurgen" sort="Thiel, Heinz Jurgen" uniqKey="Thiel H" first="Heinz-Jürgen" last="Thiel">Heinz-Jürgen Thiel</name><affiliation wicri:level="1"><nlm:aff id="aff13"><addr-line>Institute for Virology, Fachbereich Veterinärmedizin, Justus-Liebig Universität Gießen, Giessen, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute for Virology, Fachbereich Veterinärmedizin, Justus-Liebig Universität Gießen, Giessen</wicri:regionArea></affiliation></author><author><name sortKey="Schwegmann We Els, Christel" sort="Schwegmann We Els, Christel" uniqKey="Schwegmann We Els C" first="Christel" last="Schwegmann-We Els">Christel Schwegmann-We Els</name><affiliation wicri:level="1"><nlm:aff id="aff12"><addr-line>Institute of Virology, Tierärztliche Hochschule Hannover, Hannover, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, Tierärztliche Hochschule Hannover, Hannover</wicri:regionArea></affiliation></author><author><name sortKey="Pohlmann, Stefan" sort="Pohlmann, Stefan" uniqKey="Pohlmann S" first="Stefan" last="Pöhlmann">Stefan Pöhlmann</name><affiliation wicri:level="1"><nlm:aff id="aff10"><addr-line>Institute of Virology, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, Hannover Medical School, Hannover</wicri:regionArea></affiliation></author><author><name sortKey="Haas, Jurgen" sort="Haas, Jurgen" uniqKey="Haas J" first="Jürgen" last="Haas">Jürgen Haas</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University (LMU) Munich, München, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University (LMU) Munich, München</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff14"><addr-line>Division of Pathway Medicine, University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Division of Pathway Medicine, University of Edinburgh, Edinburgh</wicri:regionArea></affiliation></author><author><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Virology, University of Bonn, Bonn, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn, Bonn</wicri:regionArea></affiliation></author><author><name sortKey="Von Brunn, Albrecht" sort="Von Brunn, Albrecht" uniqKey="Von Brunn A" first="Albrecht" last="Von Brunn">Albrecht Von Brunn</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University (LMU) Munich, München, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University (LMU) Munich, München</wicri:regionArea></affiliation></author></analytic><series><title level="j">PLoS Pathogens</title><idno type="ISSN">1553-7366</idno><idno type="eISSN">1553-7374</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Perlman, S" uniqKey="Perlman S">S Perlman</name></author><author><name sortKey="Netland, J" uniqKey="Netland J">J Netland</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Peiris, Js" uniqKey="Peiris J">JS Peiris</name></author><author><name sortKey="Yuen, Ky" uniqKey="Yuen K">KY Yuen</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author><author><name sortKey="Stohr, K" uniqKey="Stohr K">K Stohr</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, Lf" uniqKey="Wang L">LF Wang</name></author><author><name sortKey="Shi, Z" uniqKey="Shi Z">Z Shi</name></author><author><name sortKey="Zhang, S" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Pathog</journal-id><journal-id journal-id-type="iso-abbrev">PLoS Pathog</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plospath</journal-id><journal-title-group><journal-title>PLoS Pathogens</journal-title></journal-title-group><issn pub-type="ppub">1553-7366</issn><issn pub-type="epub">1553-7374</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">22046132</article-id><article-id pub-id-type="pmc">3203193</article-id><article-id pub-id-type="publisher-id">PPATHOGENS-D-11-00819</article-id><article-id pub-id-type="doi">10.1371/journal.ppat.1002331</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biology</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Medicine</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Veterinary Science</subject></subj-group></article-categories><title-group><article-title>The SARS-Coronavirus-Host Interactome: Identification of Cyclophilins as Target for Pan-Coronavirus Inhibitors</article-title><alt-title alt-title-type="running-head">Identification of Pan-Coronavirus Inhibitors</alt-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Pfefferle</surname><given-names>Susanne</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Schöpf</surname><given-names>Julia</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Kögl</surname><given-names>Manfred</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Friedel</surname><given-names>Caroline C.</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Müller</surname><given-names>Marcel A.</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Carbajo-Lozoya</surname><given-names>Javier</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Stellberger</surname><given-names>Thorsten</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>von Dall’Armi</surname><given-names>Ekatarina</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Herzog</surname><given-names>Petra</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kallies</surname><given-names>Stefan</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Niemeyer</surname><given-names>Daniela</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ditt</surname><given-names>Vanessa</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kuri</surname><given-names>Thomas</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Züst</surname><given-names>Roland</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pumpor</surname><given-names>Ksenia</given-names></name><xref ref-type="aff" rid="aff9"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hilgenfeld</surname><given-names>Rolf</given-names></name><xref ref-type="aff" rid="aff9"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schwarz</surname><given-names>Frank</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zimmer</surname><given-names>Ralf</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Steffen</surname><given-names>Imke</given-names></name><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Weber</surname><given-names>Friedemann</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref><xref ref-type="aff" rid="aff11"><sup>11</sup></xref></contrib><contrib contrib-type="author"><name><surname>Thiel</surname><given-names>Volker</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Herrler</surname><given-names>Georg</given-names></name><xref ref-type="aff" rid="aff12"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Thiel</surname><given-names>Heinz-Jürgen</given-names></name><xref ref-type="aff" rid="aff13"><sup>13</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schwegmann-Weßels</surname><given-names>Christel</given-names></name><xref ref-type="aff" rid="aff12"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pöhlmann</surname><given-names>Stefan</given-names></name><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Haas</surname><given-names>Jürgen</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff14"><sup>14</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Drosten</surname><given-names>Christian</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>von Brunn</surname><given-names>Albrecht</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Bernhard-Nocht-Institute, Hamburg, Germany</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Institute of Virology, University of Bonn, Bonn, Germany</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University (LMU) Munich, München, Germany</addr-line></aff><aff id="aff4"><label>4</label><addr-line>DKFZ, Heidelberg, Germany</addr-line></aff><aff id="aff5"><label>5</label><addr-line>Institute for Informatics, LMU Munich, München, Germany</addr-line></aff><aff id="aff6"><label>6</label><addr-line>Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany</addr-line></aff><aff id="aff7"><label>7</label><addr-line>IMMH, Albert-Ludwigs-University-Freiburg, Freiburg, Germany</addr-line></aff><aff id="aff8"><label>8</label><addr-line>Institute of Immunobiology, Kantonsspital St. Gallen, Switzerland</addr-line></aff><aff id="aff9"><label>9</label><addr-line>Institute of Biochemistry, University of Luebeck, Luebeck, Germany</addr-line></aff><aff id="aff10"><label>10</label><addr-line>Institute of Virology, Hannover Medical School, Hannover, Germany</addr-line></aff><aff id="aff11"><label>11</label><addr-line>Institute of Virology, Philipps-Universität Marburg, Marburg, Germany</addr-line></aff><aff id="aff12"><label>12</label><addr-line>Institute of Virology, Tierärztliche Hochschule Hannover, Hannover, Germany</addr-line></aff><aff id="aff13"><label>13</label><addr-line>Institute for Virology, Fachbereich Veterinärmedizin, Justus-Liebig Universität Gießen, Giessen, Germany</addr-line></aff><aff id="aff14"><label>14</label><addr-line>Division of Pathway Medicine, University of Edinburgh, Edinburgh, United Kingdom</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Denison</surname><given-names>Mark R.</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1">Vanderbilt University, United States of America</aff><author-notes><corresp id="cor1">* E-mail: <email>vonbrunn@mvp.uni-muenchen.de</email> (AvB); <email>drosten@virology-bonn.de</email> (CD); <email>juergen.haas@ed.ac.uk</email> (JH)</corresp><fn fn-type="con"><p>Conceived and designed the experiments: M. Kögl, F. Weber, V. Thiel, G. Herrler, H. Thiel, C. Swegmann-Weßels, S. Pöhlmann, C. Drosten, A. von Brunn. Performed the experiments: S. Pfefferle, J. Schöpf, M. Müller, J. Carbajo-Lozoya, T. Stellberger, P. Herzong, S. Kallies, D. Niemeyer, V. Ditt, T. Kuri, R. Züst, E. von Dall'Armi, I. Steffen, A. von Brunn. Analyzed the data: M. Kögl, C. Friedel, R. Zimmer, F. Schwarz, F. Weber, V. Thiel, H. Thiel, C. Schwegmann-Weßels, S. Pöhlmann, C. Drosten, A. von Brunn. Contributed reagents/materials/analysis tools: K. Pumpor, R. Hilgenfeld, J. Haas. Wrote the paper: A. von Brunn, C. Drosten, S. Pöhlmann.</p></fn></author-notes><pub-date pub-type="collection"><month>10</month><year>2011</year></pub-date><pub-date pub-type="epub"><day>27</day><month>10</month><year>2011</year></pub-date><volume>7</volume><issue>10</issue><elocation-id>e1002331</elocation-id><history><date date-type="received"><day>8</day><month>4</month><year>2011</year></date><date date-type="accepted"><day>8</day><month>9</month><year>2011</year></date></history><permissions><copyright-statement>Pfefferle et al.</copyright-statement><copyright-year>2011</copyright-year><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p></license></permissions><abstract><p>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.</p></abstract><abstract abstract-type="summary"><title>Author Summary</title><p>Broad-range anti-infective drugs are well known against bacteria, fungi, and parasites. These pathogens maintain their own metabolism distinctive from that of the host. Broad-range drugs can be obtained by targeting elements that several of these organisms have in common. In contrast, target overlap between different viruses is minimal. The replication of viruses is highly interweaved with the metabolism of the host cell. A high potential in the development of antivirals with broad activity might therefore reside in the identification of host factors elemental to virus replication. In this work we followed a systems biology approach, screening for interactions between virus and host proteins by employing an automated yeast-two-hybrid setup. Upon binding of a viral protein to cyclophilins the screen led to the identification of the Calcineurin/NFAT pathway possibly being involved in the pathogenesis of SARS-Coronavirus. Secondly, cyclophilins were suggested to play an elemental role in virus replication since cyclosporin A inhibited replication of all Coronavirus prototype members tested. This large range of viruses includes common cold viruses, the SARS agent, as well as a range of animal viruses. For the first time this work shows that an undirected, systems-biology approach could identify a host-encoded, broad-range antiviral target.</p></abstract><counts><page-count count="15"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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|wiki= Sante
|area= SrasV1
|flux= Pmc
|étape= Curation
|type= RBID
|clé= PMC:3203193
|texte= The SARS-Coronavirus-Host Interactome: Identification of Cyclophilins as Target for Pan-Coronavirus Inhibitors
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Curation/RBID.i -Sk "pubmed:22046132" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Curation/biblio.hfd \
| NlmPubMed2Wicri -a SrasV1
| This area was generated with Dilib version V0.6.33. |  |