A recombinant receptor-binding domain of MERS-CoV in trimeric form protects human dipeptidyl peptidase 4 (hDPP4) transgenic mice from MERS-CoV infection

Virology. 2016 Dec;499:375-382. doi: 10.1016/j.virol.2016.10.005. Epub 2016 Oct 15.

Abstract

Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) was first identified in 2012, and it continues to threaten human health worldwide. No MERS vaccines are licensed for human use, reinforcing the urgency to develop safe and efficacious vaccines to prevent MERS. MERS-CoV spike protein forms a trimer, and its receptor-binding domain (RBD) serves as a vaccine target. Nevertheless, the protective efficacy of RBD in its native trimeric form has never been evaluated. In this study, a trimeric protein, RBD-Fd, was generated by fusing RBD with foldon trimerization motif. It bound strongly to the receptor of MERS-CoV, dipeptidyl peptidase 4 (DPP4), and elicited robust RBD-specific neutralizing antibodies in mice, maintaining long-term neutralizing activity against MERS-CoV infection. RBD-Fd potently protected hDPP4 transgenic mice from lethal MERS-CoV challenge. These results suggest that MERS-CoV RBD in its trimeric form maintains native conformation and induces protective neutralizing antibodies, making it a candidate for further therapeutic development.

Keywords: Foldon trimerization motif; MERS; MERS-CoV; Neutralization; Protection; Receptor-binding domain; Spike protein; hDPP4-transgenic mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / immunology
  • Coronavirus Infections / enzymology
  • Coronavirus Infections / immunology
  • Coronavirus Infections / prevention & control*
  • Coronavirus Infections / virology
  • Dipeptidyl Peptidase 4 / genetics
  • Dipeptidyl Peptidase 4 / immunology*
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Middle East Respiratory Syndrome Coronavirus / chemistry
  • Middle East Respiratory Syndrome Coronavirus / genetics
  • Middle East Respiratory Syndrome Coronavirus / immunology*
  • Protein Binding
  • Protein Domains
  • Receptors, Virus / genetics
  • Receptors, Virus / immunology*
  • Spike Glycoprotein, Coronavirus / chemistry*
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / immunology*

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Receptors, Virus
  • Spike Glycoprotein, Coronavirus
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4
  • Dpp4 protein, mouse