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

doi:10.1128/JVI.75.17.8173-8186.2001

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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 carcinoembryonicantigen family of cell adhesion molecules. In the mouse, splicevariants of CEACAM1 have either two or four immunoglobulin (Ig)domains linked through a transmembrane domain to either a shortor a long cytoplasmic tail. CEACAM1 has cell adhesion activityand acts as a signaling molecule, and long-tail isoforms inhibitthe growth of colon and prostate tumor cells in rodents. CEACAM1isoforms serve as receptors for several viral and bacterial pathogens,including the murine coronavirus mouse hepatitis virus (MHV) andHaemophilus influenzae, Neisseria gonorrhoeae, and Neisseria meningitidisin humans. To elucidate the mechanisms responsible for the manybiological activities of CEACAM1, we modified the expression ofthe mouse Ceacam1 gene in vivo. Manipulation of the Ceacam1 genein mouse embryonic stem cells that contained the Ceacam1a alleleyielded a partial knockout. We obtained one line of mice in whichthe insert in the Ceacam1a gene had sustained a recombinationevent. This resulted in the markedly reduced expression of thetwo CEACAM1a isoforms with four Ig domains, whereas the expressionof the two isoforms with two Ig domains was doubled relative tothat in wild-type BALB/c (+/+) mice. Homozygous (p/p) Ceacam1a-targetedmice (Ceacam1a $Delta$ 4D) had no gross tissue abnormalities and wereviable and fertile; however, they were more resistant to MHV A59infection and death than normal (+/+) mice. Following intranasalinoculation with MHV A59, p/p mice developed markedly fewer andsmaller lesions in the liver than +/+ or heterozygous (+/p) mice.The titers of virus produced in the livers were 50- to 100-foldlower in p/p mice than in +/p or +/+ mice. p/p mice survived adose 100-fold higher than the lethal dose of virus for +/+ mice.+/p mice were intermediate between +/+ and p/p mice in susceptibilityto liver damage, virus growth in liver, and susceptibility tokilling by MHV. Ceacam1a-targeted mice provide a new model tostudy the effects of modulation of receptor expression on susceptibilityto MHV infection invivo.

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

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