Targeted disruption of the Ceacam1 (MHVR) gene leads to reduced susceptibility of mice to mouse hepatitis virus infection

The CEACAM1 glycoproteins (formerly called biliary glycoproteins; BGP, C-CA M, CD66a, or MHVR) are members of the carcinoembryonic antigen family of ce ll adhesion molecules. In the mouse, splice variants of CEACAM1 have either two or four immunoglobulin (Ig) domains linked through a transmembrane dom ain 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 s erve 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 t he 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 t he insert in the Ceacam1a gene had sustained a recombination event. This re sulted in the markedly reduced expression of the two CEACAM1a isoforms with four Ig domains, whereas the expression of the two isoforms with two Ig do mains was doubled relative to that in wild-type BALB/c (+/+) mice. Homozygo us (p/p) Ceacam1a-targeted mice (Ceacam1a Delta 4D) had no gross tissue abn ormalities and were viable and fertile; however, they were more resistant t o MHV A59 infection and death than normal (+/+) mice. Following intranasal inoculation with MHV A59, p/p mice developed markedly fewer and smaller les ions 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 o r +/+ mice. p/p mice survived a dose 100-fold higher than the lethal dose o f virus for +/+ mice. +/p mice were intermediate between +/+ and p/p mice i n 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 infe ction in vivo.