title: The spike glycoprotein of murine coronavirus MHV-JHM mediates receptor-independent infection and spread in the central nervous systems of Ceacam1a-/- 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(-/-) 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 10(6) 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 (LD(50)) is <10(1.3) in wild-type mice and 10(3.1) in Ceacam1a(-/-) mice. For SJHM/RA59, the LD(50) is <10(1.3) in wild-type mice and 10(3.6) 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.
authors.affiliation: Department of Microbiology MS 8333, University of Colorado Health Sciences Center, 12800 E. 19th Ave., P.O. Box 6511, Aurora, CO 80045, USA.
authors.forename: Tanya A
authors.initials: TA
authors.lastname: Miura
authors.forename: Emily A
authors.initials: EA
authors.lastname: Travanty
authors.forename: Lauren
authors.initials: L
authors.lastname: Oko
authors.forename: Helle
authors.initials: H
authors.lastname: Bielefeldt-Ohmann
authors.forename: Susan R
authors.initials: SR
authors.lastname: Weiss
authors.forename: Nicole
authors.initials: N
authors.lastname: Beauchemin
authors.forename: Kathryn V
authors.initials: KV
authors.lastname: Holmes
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology / Q000821:virology; D002272:Carcinoembryonic Antigen / Q000235:genetics*; D002490:Central Nervous System / Q000821:virology*; D018352:Coronavirus Infections / Q000821:virology*; D017353:Gene Deletion; D007928:Lethal Dose 50; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D006517:Murine hepatitis virus / Q000254:growth & development* / Q000502:physiology; D064370:Spike Glycoprotein, Coronavirus; D016019:Survival Analysis; D014759:Viral Envelope Proteins / Q000235:genetics / Q000502:physiology*; D037521:Virulence Factors / Q000235:genetics / Q000502:physiology; D053586:Virus Internalization
chemical_list: D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D008562:Membrane Glycoproteins; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins; D037521:Virulence Factors