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Journal of Virology, September 2001, p. 8173-8186, Vol. 75, No. 17
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.17.8173-8186.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Targeted Disruption of the Ceacam1 (MHVR) Gene Leads to Reduced Susceptibility of Mice to Mouse Hepatitis Virus Infection

Dianna M. Blau,1 Claire Turbide,2 Michel Tremblay,2,3,7 Melanie Olson,2 Stéphanie Létourneau,2 Eva Michaliszyn,3,4 Serge Jothy,5 Kathryn V. Holmes,1 and Nicole Beauchemin2,3,6,7,*

Department of Microbiology, University of Colorado Health Sciences Center, Denver, Colorado,1 and McGill Cancer Centre2 and Departments of Biochemistry,3 Medicine,6 and Oncology,7 McGill University, Montreal, Quebec, and Amgen Institute4 and Department of Pathology, Sunnybrook Health Sciences Centre,5 Toronto, Ontario, Canada

Received 20 February 2001/Accepted 23 May 2001

The CEACAM1 glycoproteins (formerly called biliary glycoproteins; BGP, C-CAM, CD66a, or MHVR) are members of the carcinoembryonic antigen family of cell adhesion molecules. In the mouse, splice variants of CEACAM1 have either two or four immunoglobulin (Ig) domains linked through a transmembrane domain to either a short or a long cytoplasmic tail. CEACAM1 has cell adhesion activity and acts as a signaling molecule, and long-tail isoforms inhibit the growth of colon and prostate tumor cells in rodents. CEACAM1 isoforms serve as receptors for several viral and bacterial pathogens, including the murine coronavirus mouse hepatitis virus (MHV) and Haemophilus influenzae, Neisseria gonorrhoeae, and Neisseria meningitidis in humans. To elucidate the mechanisms responsible for the many biological activities of CEACAM1, we modified the expression of the mouse Ceacam1 gene in vivo. Manipulation of the Ceacam1 gene in mouse embryonic stem cells that contained the Ceacam1a allele yielded a partial knockout. We obtained one line of mice in which the insert in the Ceacam1a gene had sustained a recombination event. This resulted in the markedly reduced expression of the two CEACAM1a isoforms with four Ig domains, whereas the expression of the two isoforms with two Ig domains was doubled relative to that in wild-type BALB/c (+/+) mice. Homozygous (p/p) Ceacam1a-targeted mice (Ceacam1aDelta 4D) had no gross tissue abnormalities and were viable and fertile; however, they were more resistant to MHV A59 infection and death than normal (+/+) mice. Following intranasal inoculation with MHV A59, p/p mice developed markedly fewer and smaller lesions in the liver than +/+ or heterozygous (+/p) mice. The titers of virus produced in the livers were 50- to 100-fold lower in p/p mice than in +/p or +/+ mice. p/p mice survived a dose 100-fold higher than the lethal dose of virus for +/+ mice. +/p mice were intermediate between +/+ and p/p mice in susceptibility to liver damage, virus growth in liver, and susceptibility to killing by MHV. Ceacam1a-targeted mice provide a new model to study the effects of modulation of receptor expression on susceptibility to MHV infection in vivo.

* Corresponding author. Mailing address: McGill Cancer Centre, McGill University, McIntyre Medical Sciences Building, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6. Phone: (514) 398-3541. Fax: (514) 398-6769. E-mail: nicoleb{at}med.mcgill.ca.

Journal of Virology, September 2001, p. 8173-8186, Vol. 75, No. 17
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.17.8173-8186.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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