Coronavirus Spike Protein and Tropism Changes

Abstract

Coronaviruses (CoVs) have a remarkable potential to change tropism. This is particularly illustrated over the last 15 years by the emergence of two zoonotic CoVs, the severe acute respiratory syndrome (SARS)- and Middle East respiratory syndrome (MERS)-CoV. Due to their inherent genetic variability, it is inevitable that new cross-species transmission events of these enveloped, positive-stranded RNA viruses will occur. Research into these medical and veterinary important pathogens-sparked by the SARS and MERS outbreaks-revealed important principles of inter- and intraspecies tropism changes. The primary determinant of CoV tropism is the viral spike (S) entry protein. Trimers of the S glycoproteins on the virion surface accommodate binding to a cell surface receptor and fusion of the viral and cellular membrane. Recently, high-resolution structures of two CoV S proteins have been elucidated by single-particle cryo-electron microscopy. Using this new structural insight, we review the changes in the S protein that relate to changes in virus tropism. Different concepts underlie these tropism changes at the cellular, tissue, and host species level, including the promiscuity or adaptability of S proteins to orthologous receptors, alterations in the proteolytic cleavage activation as well as changes in the S protein metastability. A thorough understanding of the key role of the S protein in CoV entry is critical to further our understanding of virus cross-species transmission and pathogenesis and for development of intervention strategies.

Discovery of a novel swine enteric alphacoronavirus (SeACoV) in southern China

“…Since domain 0 and domain A are structurally similar and might come from a gene-duplication event (Walls et al, 2016b), we also hypothesize that either of them is likely dispensable in the S1 of CoVs. In addition, the presence of domain 0 in SeACoV/HKU2 is in line with the enteric tropism of these viruses since PEDV and TGEV also possess this domain (Hulswit et al, 2016). Future study on developing the SeACoV infectious clone and resolving the alphaCoV/betaCoV-hybrid SeACoV-S glycoprotein structure are warranted to confirm these findings.…”

“…Most recently, several chimeric SeCoV strains with a TGEV genomic backbone replaced by a PEDV spike (S) gene were identified from swine fecal samples in Europe (Akimkin et al, 2016;Belsham et al, 2016;Boniotti et al, 2016), implying that novel SeCoV pathogens could emerge by inter-CoV recombination under co-infection. The S gene encodes a glycoprotein, forming trimer projections on the viral surface, which is a major structural protein critical for CoV attachment and entry into the host cell (Hulswit et al, 2016).…”

Molecular epidemiology, evolution and phylogeny of SARS coronavirus

“…The receptorbinding motifs in the C-terminal domain of S1 are implicated in receptor recognition. Substitutions within the S1 receptor-binding domain (RBD) confers adaptability to new or orthologous entry receptors, thus altering the viral tropism (Hulswit et al, 2016). Undoubtedly, the ability to bind human ACE2 is an indispensable step in establishing cross-species transmission.…”

MERS-CoV as an emerging respiratory illness: A review of prevention methods

“…The surface spike glycoprotein (S protein) has gained the most attention because it confers receptor specificity and is the primary target for the humoral immune response during infection. It is currently the key focus of MERS-CoV vaccines and anti-viral therapeutics development efforts [42][43][44].…”