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

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.

ISG15: It's Complicated

“…This includes five PLPeISG15 complex structures. The SARS-CoV PLP was among the first viral DUBs to be recognized as possessing deISGylase activity and has been associated with the reduction of ISG15 conjugates and enhanced immune suppression [41,44,45]. Similar effects were observed in the more recently emergent MERS-CoV, suggesting an association between coronavirus pathogenicity and the presence of strong deISGylating activity [46].…”

“…This provided protection against EAV infection and demonstrated the feasibility of creating viable DUB-deficient mutant recombinant viruses as vaccine candidates, though under the conditions studied it could not be established that this provided greater benefit compared to wild-type virus. Another recent achievement demonstrated a similar decoupling of activity with PLP mutants in a SARS-CoV reverse genetics system, also providing key insights into virus immune suppression and pathogenesis [44]. Regrettably, these studies focused solely on the effect of these mutants on ubiquitination.…”

Genomic characterization of a novel SARS-CoV-2

“…Thus concluded that there was a basic connection between the nsp3 association and the inception of coronavirus infection (Hurst et al, 2013a). Besides, they investigated that NSP3 contains the papain-like protease and is regarded as significant for SARS infection (Niemeyer et al, 2018). Variations found in subjects began from Wuhan are situated in either TM1 or Y space which is profoundly saved (Hurst et al, 2013a(Hurst et al, , 2013b.…”

Probing the impact of nairovirus genomic diversity on viral ovarian tumor domain protease (vOTU) structure and deubiquitinase activity

“…In contrast, deISGylating activity appears to play a role in later stages of CCHFV infection. A recent study demonstrated a similar impact of DUB activity in viral immune suppression during the replication cycle of severe acute respiratory syndrome coronavirus (SARS-CoV) [31]. Specifically, when the DUB activity of the SARS-CoV papain-like protease (PLpro) was selectively disrupted, the virus showed increased sensitivity to IFN and slower growth kinetics.…”