Two recent HCoVs, severe acute respiratory syndrome coronaviruses (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), emerged in 2002 and 2012, respectively, causing life-threathening disease in humans. In addition, novel animal coronaviruses, such as the porcine deltacoronavirus (PDCoV) and the porcine epidemic diarrhea virus (PEDV), have recently emerged, causing great economic loss in China and the United States
Coronaviruses are enveloped, positive-strand RNA viruses with genomes approximately 30 kb in length that belong to the family Coronaviridae in the order Nidovirales. Coronaviruses infect a wide variety of mammalian and avian species, in most cases causing respiratory and intestinal tract disease. Human coronaviruses (HCoVs), such as HCoV-OC43, HCoV-NL63 and HKU1, have long been recognized as major causes of the common cold.
Coronavirus RNA synthesis is connected with formation of double-membrane vesicles and convoluted membranes. Coronavirus encode proofreading machinery, unique in the RNA virus world, to ensure the maintenance of their large genome size.
Coronavirus RNA synthesis is performed by a replication-transcription complex that includes viral and cell proteins that recognize cis-acting RNA elements mainly located in the highly structured 5′ and 3′ untranslated regions. In addition to many viral nonstructural proteins, the presence of cell nuclear proteins, the presence of cell nuclear proteins and the viral nucleocapsid protein increase virus amplification efficacy.
Replication of the coronavirus genome requires continuous RNA synthesis, whereas transcription is a discontinuous process unique among RNA viruses. Transcription includes a template switch during the synthesis of subgenomic negative-strand RNAs to add a copy of the leader sequence. Coronavirus transcription is regulated by multiple factors, including the extent of base-pairing between transcription-regulating sequence of positive and negative polarity, viral and cell protein-RNA binding, and high order RNA-RNA interactions.
These findings also indicate that it might be difficult to distinguish exposure to SARS-CoV-2 from other SARSr-CoVs in serological studies using S ectodomain trimers and that specific assays will need to be designed. The investigation results provide structural framework to identify conserved and accessible epitopes across S glycoproteins that will support ongoing vaccine design efforts. Elicitation of diverse, polyclonal Ab responses might prove key in light of the diversity of viruses circulating in animal reservoirs and in preventing the possible emergence of viral neutralization.
The investigation note that most SARS-CoV neutralizing Abs isolated to date target the SB domain and that several of them recognize the RBM and prevent receptor engagement. As the SARS-CoV-2 and SARS-CoV SB domains share 75% amino acid sequence identity, future work will be necessary to evaluate whether any of these Abs neutralize the newly emerged coronavirus.
The investigation surmise most of these Abs target the highly conserved S2 subunit (including the fusion peptide region) based on its structural similarity across SARS-CoV-2 and SARS-CoV, the lack of crosss-reactivity of several SB-directed Abs, and previous reports showing that sera from SARS-CoV-infected individuals target this region.
The striking structural similarity and sequence conservation among the SARS-CoV-2 S and SARS-CoV S glycoproteins emphasize the close relationship between these two viruses that recognize hACE2 to enter target cells. This resemblance is further strengthened by investigation finding that SARS-CoV S elicited polyclonal Ab responses, potently neutralizing SARS-CoV-2 S-mediated entry into cells.
Based on the aforementioned data correlating the binding affinity of SARS-CoV for hACE2 with the rate of transmissibility , viral replication in distinct species, and disease severity, the investigation thypothesize that the most pathogenic coronaviruses will exhibit S glycoprotein trimers spontaneously sampling closed and open conformations, as is the case for SARS-CoV-2, SARS-CoV and MERS-CoV.