Defining Spike Correlates of Coronavirus Emergence

The coronavirus spike has two major functions in the virus life cycle: receptor binding/attachment and entry/fusion via proteolytic activation. While most CoV emergence research focuses on receptor binding capacity, we believe that changes in proteolytic activation of spike is critical for zoonotic strains to become epidemic CoVs. Proteolytic activation is governed by motifs in the C-terminal of S1 (CTS1). This domain, adjacent to the receptor binding domain (RBD), harbors the S1/S2 cleavage site. A host protease in the endosome or on the cell surface must cleave this site to provide allow cleavage of S2 cleavage site leading to activation of fusion. Importantly, numerous CTS1 motifs contribute directly and indirectly to proteolytic activation of the spike. Our studies focus on changes in three areas of the CTS1: 1) the S1/S2 cleavage motif, 2) the region adjacent to the S1/S2 cleavage motif, and 3) changes in the CTS1 distal to the cleavage site. We believe that changes in these three areas help transition zoonotic CoVs to epidemics.  Defining the key motifs and understanding their mechanisms are a key to classify the threat posed by circulating zoonotic coronaviruses and respond to future CoV pandemics.