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.
Highlights
Five distinct CoVs (SARS-CoV, hCoV-NL63, hCoV-HKU-1, hCoV-OC43, hCoV-229E) cause respiratory tract illness in humans, ranging from mild common cold to deadly virus-associated pneumonia [1]
Broad-range anti-infective drugs are well known against bacteria, fungi, and parasites
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 severe acute respiratory syndrome (SARS)-Coronavirus
Summary
Five distinct CoVs (SARS-CoV, hCoV-NL63, hCoV-HKU-1, hCoV-OC43, hCoV-229E) cause respiratory tract illness in humans, ranging from mild common cold to deadly virus-associated pneumonia [1]. The agent of SARS was a novel CoV introduced into the human population from an animal reservoir, resulting in a highly lethal epidemic in 2002/2003 [1,2]. Host switching is a common feature in CoV evolution, and novel epidemic CoV can emerge anytime [1,3,5]. Because the large diversity of CoVs complicates the design of vaccines, the identification of broad-range anti-CoV drug targets might indicate alternative approaches against CoV epidemics [1].
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