The Spike Glycoprotein of Murine Coronavirus MHV-JHM Mediates Receptor-Independent Infection and Spread in the Central Nervous Systems ofCeacam1a^−/−Mice

Abstract

The MHV-JHM strain of the murine coronavirus mouse hepatitis virus is much more neurovirulent than the MHV-A59 strain, although both strains use murine CEACAM1a (mCEACAM1a) as the receptor to infect murine cells. We previously showed that Ceacam1a in Ceacam1a ؊/؊ mice. This study shows that infection and spread of MHV-JHM in the brain are dependent upon the viral spike glycoprotein. RJHM can initiate infection in the brains of Ceacam1a ؊/؊ mice, but expression of mCEACAM1a increases susceptibility to infection. The spread of infection in the brain is mCEACAM1a independent. Thus, the ability of the MHV-JHM spike to mediate mCEACAM1a-independent spread in the brain is likely an important factor in the severe neurovirulence of MHV-JHM in wild-type mice.Mouse hepatitis virus (MHV), an enveloped virus with a positive-sense RNA genome in the Coronaviridae family, has been studied widely as a model of viral pathogenesis. Strains of MHV differ in tissue tropism and virulence in mice. While MHV-A59 is both hepatotropic and neurotropic, MHV-JHM is primarily neurotropic and is much more neurovirulent than MHV-A59 (4, 22). When inoculated intracerebrally (i.c.), MHV-A59 and MHV-JHM both replicate in the central nervous systems (CNS) of susceptible mice, yet these viruses differ markedly in pathogenesis (18,34,38). MHV-A59 causes hepatitis, mild encephalitis, and subacute demyelination, whereas MHV-JHM causes acute, fatal encephalitis and, in mice that survive acute infection, chronic demyelination. The spike glycoprotein of MHV-JHM is a major determinant of neurovirulence, although other viral genes also contribute to neurovirulence (18,34,35,38). The spike glycoprotein of coronaviruses is responsible for viral attachment to the cellular receptor and fusion of the viral and cellular membranes, resulting in virus entry. In addition, the spike glycoprotein is expressed on the surface of infected cells, where it mediates cell-to-cell fusion, resulting in spread of virus by syncytium formation.

CEACAM1 regulates integrinαIIbβ3-mediated functions in platelets

“…CEACAM1 also serves as a receptor for different bacterial strains including E. coli, Salmonella typhimurium, Haemophilus influenzae, Neisseria gonorrhoeae, and Neisseria meningitidis in humans [1]. In contrast, in the mouse, it serves as a receptor for mouse hepatitis virus [2,3]. From a functional perspective, CEACAM1 is involved in a plethora of biological processes including cell morphogenesis, proliferation, migration, angiogenesis, insulin clearance, tumor suppressor, and thrombosis [4][5][6][7][8].…”

“…Platelets, Early Online:[1][2][3][4][5][6][7][8][9][10] Platelets Downloaded from informahealthcare.com by University of Otago on 07/23/15For personal use only.…”

Coronaviruses as Encephalitis - Inducing Infectious Agents

“…The magnitude of lymphocytic infiltration in mouse brain following infection by rA59 with S JHM and rA59 with S A59 is different, as S JHM induced a more efficient CNS invasion of lymphocytes than S A59 and a significant increase in the percentage of CD8 + T cells (Phillips et al, 2002). Increased immune-mediated pathology was associated with rapid viral spread (Miura et al, 2008;Wodarz & Krakauer, 2000). The recombinant virus rA59, harboring the JHM S protein (S JHM ) is not as virulent as wild-type recombinant rJHM, indicating that neurovirulence also depends on other background genes.…”

A Small Region of Porcine Hemagglutinating Encephalomyelitis Virus Spike Protein Interacts with the Neural Cell Adhesion Molecule

“…The coronavirus spike (S) protein is a key protein for determining the host and the tissue specificity of the virus, and plays an important role in coronavirus infection and pathogenicity [8,9,10]. The receptor of the coronaviral S protein is responsible for viruses entering into cells via fusion of viral envelope and the cellular membrane [11].…”