title: Soluble receptor-mediated targeting of mouse hepatitis coronavirus to the human epidermal growth factor receptor.
abstract: The mouse hepatitis coronavirus (MHV) infects murine cells by binding of its spike (S) protein to murine CEACAM1a. The N-terminal part of this cellular receptor (soR) is sufficient for S binding and for subsequent induction of the conformational changes required for virus-cell membrane fusion. Here we analyzed whether these characteristics can be used to redirect MHV to human cancer cells. To this end, the soR domain was coupled to single-chain monoclonal antibody 425, which is directed against the human epidermal growth factor receptor (EGFR), resulting in a bispecific adapter protein (soR-425). The soR and soR-425 proteins, both produced with the vaccinia virus system, were able to neutralize MHV infection of murine LR7 cells. However, only soR-425 was able to target MHV to human EGFR-expressing cancer cells. Interestingly, the targeted infections induced syncytium formation. Furthermore, the soR-425-mediated infections were blocked by heptad repeat-mimicking peptides, indicating that virus entry requires the regular S protein fusion process. We conclude that the specific spike-binding property of the CEACAM1a N-terminal fragment can be exploited to direct the virus to selected cells by linking it to a moiety able to bind a receptor on those cells. This approach might be useful in the development of tumor-targeted coronaviruses.
authors.affiliation: Virology Division, Department of Infectious Diseases & Immunology, Utrecht University, 3584 CL Utrecht, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Würdinger
authors.forename: M H
authors.initials: MH
authors.lastname: Verheije
authors.forename: K
authors.initials: K
authors.lastname: Broen
authors.forename: B J
authors.initials: BJ
authors.lastname: Bosch
authors.forename: B J
authors.initials: BJ
authors.lastname: Haijema
authors.forename: C A M
authors.initials: CA
authors.lastname: de Haan
authors.forename: V W
authors.initials: VW
authors.lastname: van Beusechem
authors.forename: W R
authors.initials: WR
authors.lastname: Gerritsen
authors.forename: P J M
authors.initials: PJ
authors.lastname: Rottier
mesh_terms: D000818:Animals; D018352:Coronavirus Infections / Q000276:immunology / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D006517:Murine hepatitis virus / Q000502:physiology*; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000502:physiology*
chemical_list: D008562:Membrane Glycoproteins; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins; C578557:spike glycoprotein, SARS-CoV; C578553:spike protein, mouse hepatitis virus; D066246:ErbB Receptors