ABSTRACT Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) causes a severe respiratory disease in humans. The MERS-CoV spike (S) glycoprotein mediates viral entry into target cells. For this, MERS-CoV S engages the host cell protein dipeptidyl peptidase 4 (DPP4, CD26) and the interface between MERS-CoV S and DPP4 has been resolved on the atomic level. Here, we asked whether naturally-occurring polymorphisms in DPP4, that alter amino acid residues required for MERS-CoV S binding, influence cellular entry of MERS-CoV. By screening of public databases, we identified fourteen such polymorphisms. Introduction of the respective mutations into DPP4 revealed that all except one (Δ346-348) were compatible with robust DPP4 expression. Four polymorphisms (K267E, K267N, A291P and Δ346-348) strongly reduced binding of MERS-CoV S to DPP4 and S protein-driven host cell entry, as determined using soluble S protein and S protein bearing rhabdoviral vectors, respectively. Two polymorphisms (K267E and A291P) were analyzed in the context of authentic MERS-CoV and were found to attenuate viral replication. Collectively, we identified naturally-occurring polymorphisms in DPP4 that negatively impact cellular entry of MERS-CoV and might thus modulate MERS development in infected patients.
【저자키워드】 spike glycoprotein, Polymorphisms, Dipeptidyl peptidase 4, Middle East respiratory syndrome Coronavirus, Receptor binding, 【초록키워드】 coronavirus, Mutation, S protein, polymorphism, MERS, MERS-CoV, viral entry, DPP4, Protein, viral replication, humans, glycoprotein, cellular entry, expression, binding, Middle East, target cells, host cell, infected patients, atomic level, severe respiratory disease, syndrome, CD26, vectors, amino acid residue, Alter, robust, analyzed, required, reduced, modulate, cause, resolved, engage, attenuate, asked, 【제목키워드】 Middle East, host cell, respiratory syndrome coronavirus, reduce,