The SARS-Coronavirus-host interactome: Identification of cyclophilins as target for pan-Coronavirus inhibitors

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 WeberVolker Thiel, Georg Herrler, Heinz Jürgen Thiel, Christel Schwegmann-Weßels, Stefan Pöhlmann, Jürgen Haas*, Christian Drosten, Albrecht von Brunn

*Korrespondierende/r Autor/-in für diese Arbeit
77 Zitate (Scopus)

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.

OriginalspracheEnglisch
Aufsatznummere1002331
ZeitschriftPLoS Pathogens
Jahrgang7
Ausgabenummer10
ISSN1553-7366
DOIs
PublikationsstatusVeröffentlicht - 01.10.2011

Strategische Forschungsbereiche und Zentren

  • Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)

Coronavirus-Bezug

  • Forschung zu SARS-CoV-2 / COVID-19

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