title: The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors.
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.
authors: Bernhard-Nocht-Institute, Hamburg, Germany.
authors: Susanne
authors: S
authors: Pfefferle
authors: Julia
authors: J
authors: Schöpf
authors: Manfred
authors: M
authors: Kögl
authors: Caroline C
authors: CC
authors: Friedel
authors: Marcel A
authors: MA
authors: Müller
authors: Javier
authors: J
authors: Carbajo-Lozoya
authors: Thorsten
authors: T
authors: Stellberger
authors: Ekatarina
authors: E
authors: von Dall'Armi
authors: Petra
authors: P
authors: Herzog
authors: Stefan
authors: S
authors: Kallies
authors: Daniela
authors: D
authors: Niemeyer
authors: Vanessa
authors: V
authors: Ditt
authors: Thomas
authors: T
authors: Kuri
authors: Roland
authors: R
authors: Züst
authors: Ksenia
authors: K
authors: Pumpor
authors: Rolf
authors: R
authors: Hilgenfeld
authors: Frank
authors: F
authors: Schwarz
authors: Ralf
authors: R
authors: Zimmer
authors: Imke
authors: I
authors: Steffen
authors: Friedemann
authors: F
authors: Weber
authors: Volker
authors: V
authors: Thiel
authors: Georg
authors: G
authors: Herrler
authors: Heinz-Jürgen
authors: HJ
authors: Thiel
authors: Christel
authors: C
authors: Schwegmann-Wessels
authors: Stefan
authors: S
authors: Pöhlmann
authors: Jürgen
authors: J
authors: Haas
authors: Christian
authors: C
authors: Drosten
authors: Albrecht
authors: A
authors: von Brunn
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D018938:Caco-2 Cells; D002522:Chlorocebus aethiops; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D019169:Jurkat Cells; D011480:Protease Inhibitors / Q000494:pharmacology; D025941:Protein Interaction Mapping; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects / Q000472:pathogenicity*; D045169:Severe Acute Respiratory Syndrome / Q000188:drug therapy*; D020798:Two-Hybrid System Techniques; D014709:Vero Cells; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D014764:Viral Proteins; D016572:Cyclosporine; D021983:Cyclophilins