Heart-nosed bat alphacoronaviruses use human CEACAM6 to enter cells

Identifying viruses with zoonotic potential based on their ability to enter human cells is a critical component of pandemic prediction, prevention and preparedness. Using a computational approach that retains maximum phylogenetic diversity, we selected an optimal subset of alphacoronavirus spike proteins and screened these against broad coronavirus receptor libraries. Interestingly, most selected spikes did not use any of the established coronavirus receptors. However, the pseudotyped spike of Cardioderma cor coronavirus (CcCoV) KY43 could enter human cells. Using a recombinant CcCoV receptor binding domain (RBD) and a human receptor screening platform, we identified direct interactions with human CEACAM proteins 3, 5, and 6.Over-expression of human CEACAM6 – a protein widely expressed in the human lung – conferred permissivity to otherwise refractory human cells. A crystal structure showed that the RBD binds the N-terminal IgV-like domain of human CEACAM6. Immune-surveillance studies in sera from individuals from the Taveta region of Kenya, where CcCoV KY43 was identified, did not show significant evidence of recent spillover. Wider characterisation of alphacoronaviruses related to CcCoV KY43 identified human CEACAM6 usage by two other CcCoVs collected in Kenya, as well as a more restricted non-human CEACAM6 tropism for viruses isolated in Rhinophulus bats from Russia and China. Thus, CEACAM6-using alphacoronaviruses are likely geographically widespread, with viruses from East Africa showing potential for transmission to humans.