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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
(Ceacam1a
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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