The SARS-Coronavirus-Host Interactome: Identification of Cyclophilins as Target for Pan-Coronavirus Inhibitors

• DOI: 10.1371/journal.ppat.1002331
• Publication Date: 2011-10-27T20:57:14Z
• Authors: Susanne Pfefferle; Julia Schöpf; Manfred Kögl; Caroline C. Friedel; Marcel A. Müller; Javier Carbajo-Lo...; Thorsten Stellberger; Ekatarina von Dal...; 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 Schwegma...; Stefan Pöhlmann; Jürgen Haas; Christian Drosten; Albrecht von Brunn
• Keywords: Coronavirus; NFAT; Interactome; Coronaviridae; Betacoronavirus

Coronaviruses (CoVs) are important human and animal pathogens that induce fatal respiratory, gastrointestinal neurological disease. The outbreak of the severe acute respiratory syndrome (SARS) in 2002/2003 has demonstrated vulnerability to (Coronavirus) CoV epidemics. Neither vaccines nor therapeutics available against CoVs. Knowledge host cell proteins take part pivotal virus-host interactions could define broad-spectrum antiviral targets. In this study, we used a systems biology approach employing genome-wide yeast-two hybrid interaction screen identify immunopilins (PPIA, PPIB, PPIH, PPIG, FKBP1A, FKBP1B) as partners non-structural protein 1 (Nsp1). These molecules modulate Calcineurin/NFAT pathway plays an role immune activation. Overexpression NSP1 infection with live SARS-CoV strongly increased signalling through enhanced induction interleukin 2, compatible late-stage immunopathogenicity long-term cytokine dysregulation observed SARS cases. Conversely, inhibition cyclophilins by cyclosporine A (CspA) blocked replication CoVs all genera, including SARS-CoV, CoV-229E -NL-63, feline CoV, well avian infectious bronchitis virus. Non-immunosuppressive derivatives CspA might serve broad-range inhibitors applicable emerging ubiquitous humans livestock.