Distinct Roles for Sialoside and Protein Receptors in Coronavirus Infection

Qing, Enya; Hantak, Michael; Perlman, Stanley; Gallagher, Tom

This study revealed S-protein mutations that may endow CoVs with expanded tropisms, beyond that determined by prototype proteinaceous CoV receptors. The JHM-CoV mutation G176E, engineered to reflect sialate-utilizing B-CoV, increased viral S-protein binding to cells, as well as S-protein-mediated membrane fusion, independently of mCEACAM. The MERS-CoV mutation N222D, an adaptation for virus growth in mouse lungs (58) , operated remarkably similar to the JHM-CoV G176E change, with mutant S proteins showing increased hDPP4-independent cell binding and cell fusion. Our findings fit with the hypothesis that viruses with these mutations bind relatively tightly to sialoside receptors. However, it is clear that the changes are not present in currently identified sialoside-binding sites (18, 54) , which raises alternative hypotheses that include mutation-induced allosteric restructuring of sialoside-binding sites. Alternatively, the mutations may restructure distinct receptor-or coreceptor-binding sites, such as presumed binding sites for orthologous CEACAMs on MHV S proteins (69), or sites for CEACAM5 (70) or GRP78 (71) on MERS-CoV S proteins.