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Journal of Virology, January 2008, p. 755-763, Vol. 82, No. 2
0022-538X/08/$08.00+0     doi:10.1128/JVI.01851-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Spike Glycoprotein of Murine Coronavirus MHV-JHM Mediates Receptor-Independent Infection and Spread in the Central Nervous Systems of Ceacam1a–/– Mice{triangledown}

Tanya A. Miura,1 Emily A. Travanty,1 Lauren Oko,1 Helle Bielefeldt-Ohmann,2 Susan R. Weiss,3 Nicole Beauchemin,4 and Kathryn V. Holmes1*

Department of Microbiology, University of Colorado Health Sciences Center, Aurora, Colorado 80045,1 Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado,2 Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania,3 McGill Cancer Centre, McGill University, Montreal, Quebec, Canada4

Received 22 August 2007/ Accepted 1 November 2007

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–/– mice are completely resistant to MHV-A59 infection (E. Hemmila et al., J. Virol. 78:10156-10165, 2004). In vitro, MHV-JHM, but not MHV-A59, can spread from infected murine cells to cells that lack mCEACAM1a, a phenomenon called receptor-independent spread. To determine whether MHV-JHM could infect and spread in the brain independent of mCEACAM1a, we inoculated Ceacam1a–/– mice. Although Ceacam1a–/– mice were completely resistant to i.c. inoculation with 106 PFU of recombinant wild-type MHV-A59 (RA59) virus, these mice were killed by recombinant MHV-JHM (RJHM) and a chimeric virus containing the spike of MHV-JHM in the MHV-A59 genome (SJHM/RA59). Immunohistochemistry showed that RJHM and SJHM/RA59 infected all neural cell types and induced severe microgliosis in both Ceacam1a–/– and wild-type mice. For RJHM, the 50% lethal dose (LD50) is <101.3 in wild-type mice and 103.1 in Ceacam1a–/– mice. For SJHM/RA59, the LD50 is <101.3 in wild-type mice and 103.6 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.

* Corresponding author. Mailing address: Department of Microbiology MS 8333, University of Colorado Health Sciences Center, 12800 E. 19th Ave., P.O. Box 6511, Aurora, CO 80045. Phone: (303) 724-4231. Fax: (303) 724-4226. E-mail: kathryn.holmes{at}uchsc.edu

{triangledown} Published ahead of print on 14 November 2007.

Journal of Virology, January 2008, p. 755-763, Vol. 82, No. 2
0022-538X/08/$08.00+0     doi:10.1128/JVI.01851-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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