Article

Ceacam1a−/− Mice Are Completely Resistant to Infection by Murine Coronavirus Mouse Hepatitis Virus A59

Department of Microbiology, University of Colorado Health Sciences Center, Denver, USA.
Journal of Virology (Impact Factor: 4.44). 10/2004; 78(18):10156-65. DOI: 10.1128/JVI.78.18.10156-10165.2004
Source: PubMed

ABSTRACT

CEACAM1a glycoproteins are members of the immunoglobulin (Ig) superfamily and the carcinoembryonic antigen family. Isoforms
expressing either two or four alternatively spliced Ig-like domains in mice have been found in a number of epithelial, endothelial,
or hematopoietic tissues. CEACAM1a functions as an intercellular adhesion molecule, an angiogenic factor, and a tumor cell
growth inhibitor. Moreover, the mouse and human CEACAM1a proteins are targets of viral or bacterial pathogens, respectively,
including the murine coronavirus mouse hepatitis virus (MHV), Haemophilus influenzae, Neisseria gonorrhoeae, and Neisseria meningitidis, as well as Moraxella catarrhalis in humans. We have shown that targeted disruption of the Ceacam1a (MHVR) gene resulting in a partial ablation of the protein in mice (p/p mice) led to reduced susceptibility to MHV-A59 infection
of the modified mice in the BALB/c background. We have now engineered and produced a Ceacam1a−/− mouse that exhibits complete ablation of the CEACAM1a protein in every tissue where it is normally expressed. We report that
3-week-old Ceacam1a−/− mice in the C57BL/6 genetic background are fully resistant to MHV-A59 infection by both intranasal and intracerebral routes.
Whereas virus-inoculated wild-type +/+ C57BL/6 mice showed profound liver damage and spinal cord demyelination under these
conditions, Ceacam1a−/− mice displayed normal livers and spinal cords. Virus was recovered from liver and spinal cord tissues of +/+ mice but not
of −/− mice. These results indicate that CEACAM1a is the sole receptor for MHV-A59 in both liver and brain and that its deletion
from the mouse renders the mouse completely resistant to infection by this virus.

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    • "CC1 functions as an adhesion molecule and contributes to the maintenance of normal tissue homeostasis (Gray-Owen and Blumberg, 2006). In addition, CC1 is an angiogenesis modulator (Horst et al., 2006), a regulator of insulin metabolism (Poy et al., 2002; Xu et al., 2009), and innate and adaptive immune responses (Gray-Owen and Blumberg, 2006) as well as a microbial and viral receptor (Hemmila et al., 2004; Gray-Owen and Blumberg, 2006). With respect to tumor development, CC1 functions as a growth inhibitor in a number of early solid neoplasms including tumors in the colon (Neumaier et al., 1993), prostate (Busch et al., 2002), liver (Laurie et al., 2005), endometrium (Bamberger et al., 1998), bladder (Oliveira- Ferrer et al., 2004) and breast (Kirshner et al., 2003). "
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    ABSTRACT: Liver metastasis is the predominant cause of colorectal cancer (CRC)-related mortality in developed countries. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a cell adhesion molecule with reduced expression in early phases of CRC development and thus functions as a tumor growth inhibitor. However, CEACAM1 is upregulated in metastatic colon cancer, suggesting a bimodal role in CRC progression. To investigate the role of this protein in the host metastatic environment, Ceacam1(-/-) mice were injected intrasplenically with metastatic MC38 mouse CRC cells. A significant reduction in metastatic burden was observed in Ceacam1(-/-) compared with wild-type (WT) livers. Intravital microscopy showed decreased early survival of MC38 cells in Ceacam1(-/-) endothelial environment. Metastatic cell proliferation within the Ceacam1(-/-) livers was also diminished. Bone marrow-derived cell recruitment, attenuation of immune infiltrates and diminished CCL2, CCL3 and CCL5 chemokine production participated in the reduced Ceacam1(-/-) metastatic phenotype. Transplantations of WT bone marrow (BM) into Ceacam1(-/-) mice fully rescued metastatic development, whereas Ceacam1(-/-) BM transfer into WT mice showed reduced metastatic burden. Chimeric immune cell profiling revealed diminished recruitment of CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSCs) to Ceacam1(-/-) metastatic livers and adoptive transfer of MDSCs confirmed the involvement of these immune cells in reduction of liver metastasis. CEACAM1 may represent a novel metastatic CRC target for treatment.Oncogene advance online publication, 2 April 2012; doi:10.1038/onc.2012.112.
    Full-text · Article · Apr 2012 · Oncogene
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    • "CC1 functions as an adhesion molecule and contributes to the maintenance of normal tissue homeostasis (Gray-Owen and Blumberg, 2006). In addition, CC1 is an angiogenesis modulator (Horst et al., 2006), a regulator of insulin metabolism (Poy et al., 2002; Xu et al., 2009), and innate and adaptive immune responses (Gray-Owen and Blumberg, 2006) as well as a microbial and viral receptor (Hemmila et al., 2004; Gray-Owen and Blumberg, 2006). With respect to tumor development, CC1 functions as a growth inhibitor in a number of early solid neoplasms including tumors in the colon (Neumaier et al., 1993), prostate (Busch et al., 2002), liver (Laurie et al., 2005), endometrium (Bamberger et al., 1998), bladder (Oliveira- Ferrer et al., 2004) and breast (Kirshner et al., 2003). "

    Full-text · Article · Apr 2012 · Oncogene research
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    • "Two other molecules, CEACAM2 (Nedellec et al., 1994) and pregnancy-specific glycoprotein (PSG; Chen et al., 1995), have so far been reported to work as MHV receptor. These proteins, however, seem unlikely to function as an MHV receptor in the mouse, since CEACAM1 knockout mice produced in Beauchemin lab showed complete resistance to MHV-A59 infection (Hemmila et al., 2004),. Moreover, as there are no substantial differences in amino acid sequences in those two receptor proteins expressed in B6 and SJL, there is little possibility that those proteins are involved in the differences of MHV susceptibility between SJL and chimeric mice. "
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    ABSTRACT: In this review, we report that the receptor of mouse hepatitis virus (MHV), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), is an important determinant of mouse susceptibility to MHV infection. This finding was revealed by using mouse strains with two different allelic forms of the MHV receptor, Ceacam1a and Ceacam1b. Although previous studies indicated that susceptibility is determined by a single gene, Ceacam1, our recent work in gene-replaced mice with chimeric Ceacam1 pointed toward the involvement of other host factors (genes) in the susceptibility. Studies on mouse susceptibility to MHV, as well as the factors involved in their susceptibility, are overviewed.
    Full-text · Article · Feb 2012 · Frontiers in Microbiology
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