The papain-like protease determines a virulence trait that varies among members of the SARS-coronavirus species.

Daniela Niemeyer,Ronald Dijkman,Marcel A Müller,Andrea Sieberg,Kirstin Mösbauer,Christian Drosten,Robert C Mettelman,Susan C Baker,Anna M Mielech,Eva M Klein

doi:10.1371/journal.ppat.1007296

Abstract

SARS-coronavirus (CoV) is a zoonotic agent derived from rhinolophid bats, in which a plethora of SARS-related, conspecific viral lineages exist. Whereas the variability of virulence among reservoir-borne viruses is unknown, it is generally assumed that the emergence of epidemic viruses from animal reservoirs requires human adaptation. To understand the influence of a viral factor in relation to interspecies spillover, we studied the papain-like protease (PLP) of SARS-CoV. This key enzyme drives the early stages of infection as it cleaves the viral polyprotein, deubiquitinates viral and cellular proteins, and antagonizes the interferon (IFN) response. We identified a bat SARS-CoV PLP, which shared 86% amino acid identity with SARS-CoV PLP, and used reverse genetics to insert it into the SARS-CoV genome. The resulting virus replicated like SARS-CoV in Vero cells but was suppressed in IFN competent MA-104 (3.7-fold), Calu-3 (2.6-fold) and human airway epithelial cells (10.3-fold). Using ectopically-expressed PLP variants as well as full SARS-CoV infectious clones chimerized for PLP, we found that a protease-independent, anti-IFN function exists in SARS-CoV, but not in a SARS-related, bat-borne virus. This PLP-mediated anti-IFN difference was seen in primate, human as well as bat cells, thus independent of the host context. The results of this study revealed that coronavirus PLP confers a variable virulence trait among members of the species SARS-CoV, and that a SARS-CoV lineage with virulent PLPs may have pre-existed in the reservoir before onset of the epidemic.

Highlights

The coronaviruses (CoV, family Coronaviridae) are among the most relevant groups of viruses with zoonotic potential
Phenotypic characterization of important viral functions will be necessary to identify virulence traits that determine the potential of viral emergence
As proof-of-principle, the present study demonstrates relevant functional differences between one of the main host immune antagonists of batborne viruses that belong to the same virus species as the epidemic agent of severe acute respiratory syndrome (SARS)

Summary

Introduction

The coronaviruses (CoV, family Coronaviridae) are among the most relevant groups of viruses with zoonotic potential. The Middle East respiratory syndrome coronavirus (MERSCoV) is a zoonotic agent that is frequently and repeatedly acquired by humans upon contact with dromedary camels in the Arabian Peninsula and parts of Africa [5, 6]. This virus seems to cause only limited human-to-human transmission, but is considered a major threat to global public health due to recurring nosocomial outbreaks that may facilitate onward adaptation to humans [7,8,9]. The severe acute respiratory syndrome (SARS)-CoV caused an epidemic with sustained human-to-human transmission during 2002 to 2003 in China and other countries, involving more than 8,000 notified infections with a case fatality proportion of about 10% [10, 11]

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Conclusion