Distinct Roles for Sialoside and Protein Receptors in Coronavirus Infection

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

MERS-CoV S1B domains bind to host protein (hDPP4) receptors (22) (23) (24) , and MERS-CoV S1A domains bind to host sialic acids (21) . This raised the question of whether MERS-CoV spikes can catalyze cell fusions after the binding of their S1A domains to cells, and independently of high-affinity protein receptors, similar to the JHM-CoV spikes. To address this question, MERS-CoV S-mediated cell-cell fusions were measured by DSP 1-7 ϪDSP 8 -11 complementation (Fig. 5A ) and quantified by measuring Rluc signals (Fig. 5B ). Of note, syncytial development mediated by MERS-CoV S proteins did not require hDPP4 but did require the S-protein-activating protease human TM-PRSS2 (hTMPRSS2) (Fig. 5B ). The catalytically inactive TMPRSS2(S441A) did not facilitate cell-cell fusion (Fig. 5B ). The MERS S-mediated cell fusions contrasted with those generated by HCoV-229E S proteins, which do not bind sialic acids (21) . 229E S-mediated fusions absolutely required target-cell human aminopeptidase N (hAPN) receptors (Fig. 5B ). Thus, with sufficient cell-surface protease activities, the primary hDPP4 receptor was dispensable, conceivably because the secondary sialate-binding S1A RBDs can operate at a stage in the process.