| The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in humans proved that coronaviruses are a source of new zoonotic diseases. The interactions of the coronavirus spike glycoprotein on the viral envelope with a receptor glycoprotein on the cell surface are important determinants of host range. When SARSCoV emerged, I studied the binding of the S protein to cells to identify its receptor. I showed that SARS-CoV did not use aminopeptidase N (APN) as a receptor, and with colleagues, I discovered that CD209L, a C-type lectin, can serve as a receptor for SARSCoV, even though it is less efficient in promoting SARS-CoV entry than angiotensin-converting enzyme 2 (ACE2), the principal receptor for SARS-CoV.; I analyzed the spike-receptor interactions of coronaviruses of humans, pigs, dogs and cats in phylogenetic group 1 that use APN of their normal host as receptors. These viruses naturally cause disease in only one species, but in cell culture, they can also use feline APN (fAPN) for entry. I identified small species-specific differences in APN, such as a glycan near residue 288, and a few critical residues, like T742, that were essential for the specificity of binding and entry of human, feline, canine or porcine coronaviruses. I showed that residues 500-700 of the spike protein of feline coronavirus (FCoV) bound specifically to fAPN and constitute the FCoV receptor binding domain (RBD) for fAPN. When I substituted five residues in the FCoV RBD with residues from the spike of porcine coronavirus, TGEV, the resulting mutant RBD bound porcine cells, and still bound to fAPN. Thus, small differences in the RBDs of feline and porcine coronavirus spikes determine their receptor binding specificities. I propose that the host ranges for coronaviruses in group 1 and for SARS-CoV are determined largely by the ability of the viral spike protein to recognize small, species-specific differences in orthologous receptor protein(s). Coronaviruses may emerge into new species by acquiring mutations in their RBDs that allow them to bind to an orthologous receptor in a new host, and then adapt for efficient binding to this new receptor and for efficient transmission within the new species. |
