Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC

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Abstract

Most human coronaviruses cause mild upper respiratory tract disease but may be associated with more severe pulmonary disease in immunocompromised individuals1. However, SARS coronavirus caused severe lower respiratory disease with nearly 10% mortality and evidence of systemic spread2. Recently, another coronavirus (human coronavirus-Erasmus Medical Center (hCoV-EMC)) was identified in patients with severe and sometimes lethal lower respiratory tract infection3,4. Viral genome analysis revealed close relatedness to coronaviruses found in bats5. Here we identify dipeptidyl peptidase 4 (DPP4; also known as CD26) as a functional receptor for hCoV-EMC. DPP4 specifically co-purified with the receptor-binding S1 domain of the hCoV-EMC spike protein from lysates of susceptible Huh-7 cells. Antibodies directed against DPP4 inhibited hCoV-EMC infection of primary human bronchial epithelial cells and Huh-7 cells. Expression of human and bat (Pipistrellus pipistrellus) DPP4 in non-susceptible COS-7 cells enabled infection by hCoV-EMC. The use of the evolutionarily conserved DPP4 protein from different species as a functional receptor provides clues about the host range potential of hCoV-EMC. In addition, it will contribute critically to our understanding of the pathogenesis and epidemiology of this emerging human coronavirus, and may facilitate the development of intervention strategies.

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Figure 1: Binding of hCoV-EMC S1 to cells is correlated with infection of hCoV-EMC.
Figure 2: hCoV-EMC S1 binding to DPP4.
Figure 3: DPP4 is present on hCoV-EMC-susceptible cell lines and human bronchiolar epithelial cells.
Figure 4: DPP4 is essential for virus infection.

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Primary accessions

GenBank/EMBL/DDBJ

Data deposits

The P. pipistrellus bat DPP4 sequence has been deposited in GenBank/EMBL/DDBJ under accession number KC249974.

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Acknowledgements

We thank E. Snijder for providing the anti-SARS-CoV NSP4 antibody, and E. Kindler, H. Jónsdóttir, R. Rodriguez, T. Bestebroer, S. Pas, G. Arron, M. van Velzen and W. Ouwendijk for technical assistance. This work was supported by a fellowship from China Scholarship Council to H.M. The study was financed by the European Union FP7 project EMPERIE (contract number 223498), ANTIGONE (contract number 278976), the Swiss National Science Foundation (31003A_132898) and the 3R Research Foundation Switzerland (Project 128-11). C.D. was supported by the German Research Foundation (DFG grant DR 772/3-1, KA1241/18-1) and the German Ministry of Education and Research (BMBF SARS II).

Author information

B.J.B., V.S.R. and B.L.H. designed and coordinated the study. B.J.B. and B.L.H. contributed equally to the study. V.S.R., H.M., S.L.S., D.H.W.D., M.A.M., R.D., D.M., B.J.B. and B.L.H conducted the experiments. A.Z. provided the virus, and R.A.M.F., J.A.A.D., V.T., C.D., A.D.M.E.O. and P.J.M.R. supervised part of the experiments. All authors contributed to the interpretations and conclusions presented. B.J.B. and B.L.H. wrote the manuscript, and A.D.M.E.O. and P.J.M.R. participated in editing it.

Correspondence to Berend Jan Bosch or Bart L. Haagmans.

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Competing interests

V.S.R., B.J.B., R.A.M.F., A.D.M.E.O. and B.L.H. are inventors on a patent application related to this work.

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Raj, V., Mou, H., Smits, S. et al. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 495, 251–254 (2013) doi:10.1038/nature12005

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