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Journal of Virology, November 2006, p. 10909-10918, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.00950-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cooperative Involvement of the S1 and S2 Subunits of the Murine Coronavirus Spike Protein in Receptor Binding and Extended Host Range{triangledown}

Cornelis A. M. de Haan,* Eddie te Lintelo, Zhen Li,{dagger} Matthijs Raaben, Tom Wurdinger, Berend Jan Bosch, and Peter J. M. Rottier

Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, and Institute of Biomembranes, Utrecht University, Utrecht, The Netherlands

Received 10 May 2006/ Accepted 26 August 2006

To study the process of spike (S)-receptor interaction during coronavirus entry, we evaluated the contributions of mutations in different regions of the murine hepatitis virus (MHV) S protein to natural receptor murine carcinoembryonic antigen-related cell adhesion molecule 1a (CEACAM1a) dependence and to the acquisition of extended host range. Extended-host-range variants of MHV strain A59 were previously obtained from persistently infected cells (J. H. Schickli, B. D. Zelus, D. E. Wentworth, S. G. Sawicki, and K. V. Holmes, J. Virol. 71:9499-9504, 1997). These variant viruses contain several mutations in the S protein that confer to the viruses the ability to enter cells in a heparan sulfate-dependent manner (C. A. de Haan, Z. Li, E. te Lintelo, B. J. Bosch, B. J. Haijema, and P. J. M. Rottier, J. Virol. 79:14451-14456, 2005). While the parental MHV-A59 is fully dependent on murine CEACAM1a for its entry, viruses carrying the variant mutations in the amino-terminal part of their S protein had become dependent on both CEACAM1a and heparan sulfate. Substitutions in a restricted, downstream part of the S protein encompassing heptad repeat region 1 (HR1) and putative fusion peptide (FP) did not alter the CEACAM1a dependence. However, when the mutations in both parts of the S protein were combined, the resulting viruses became independent of CEACAM1a and acquired the extended host range. In addition, these viruses showed a decreased binding to and inhibition by soluble CEACAM1a. The observations suggest that the amino-terminal region of the S protein, including the receptor-binding domain, and a region in the central part of the S protein containing HR1 and FP, i.e., regions far apart in the linear sequence, communicate and may even interact physically in the higher-order structure of the spike.

* Corresponding author. Mailing address: Virology Division, Department of Infectious Diseases and Immunology, Yalelaan 1, 3584 CL Utrecht, The Netherlands. Phone: 31-30-2534195. Fax: 31-30-2536723. E-mail: c.a.m.dehaan{at}vet.uu.nl.

{triangledown} Published ahead of print on 6 September 2006.

{dagger} Present address: Institute of Animal Science and Veterinary Medicine, Shanghai Academy of Agricultural Science, Beidi Road 2901, Shanghai 201106, People's Republic of China.

Journal of Virology, November 2006, p. 10909-10918, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.00950-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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