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

Publication

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

Journal Paper/Review - Oct 27, 2011

Pfefferle Susanne, Hilgenfeld Rolf, Schwarz Frank, Zimmer Ralf, Steffen Imke, Weber Friedemann, Thiel Volker, Herrler Georg, Thiel Heinz-Jürgen, Schwegmann-Weßels Christel, Pöhlmann Stefan, Haas Jürgen, Drosten Christian, Pumpor Ksenia, Züst Roland, Schöpf Julia, Kögl Manfred, Friedel Caroline C, Müller Marcel A, Carbajo-Lozoya Javier, Stellberger Thorsten, von Dall'armi Ekatarina, Herzog Petra, Kallies Stefan, Niemeyer Daniela, Ditt Vanessa, Kuri Thomas, von Brunn Albrecht

Citation

Pfefferle S, Hilgenfeld R, Schwarz F, Zimmer R, Steffen I, Weber F, Thiel V, Herrler G, Thiel H, Schwegmann-Weßels C, Pöhlmann S, Haas J, Drosten C, Pumpor K, Züst R, Schöpf J, Kögl M, Friedel C, Müller M, Carbajo-Lozoya J, Stellberger T, von Dall'armi E, Herzog P, Kallies S, Niemeyer D, Ditt V, Kuri T, von Brunn A. The SARS-Coronavirus-Host Interactome: Identification of Cyclophilins as Target for Pan-Coronavirus Inhibitors. PLoS Pathog 2011; 7:e1002331.

Type

Journal Paper/Review (English)

Journal

PLoS Pathog 2011; 7

Publication Date

Oct 27, 2011

Issn Electronic

1553-7374

Pages

e1002331

Brief description/objective

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.