title: Murine coronavirus neuropathogenesis: determinants of virulence.
abstract: Murine coronavirus, mouse hepatitis virus (MHV), causes various diseases depending on the strain and route of inoculation. Both the JHM and A59 strains, when inoculated intracranially or intranasally, are neurovirulent. Comparison of the highly virulent JHM isolate, JHM.SD, with less virulent JHM isolates and with A59 has been used to determine the mechanisms and genes responsible for high neuropathogenicity of MHV. The focus of this review is on the contributions of viral spread, replication, and innate and adaptive immunity to MHV neuropathogenesis. JHM.SD spreads more quickly among neurons than less neurovirulent MHVs, and is able to spread in the absence of the canonical MHV receptor, CEACAM1a. The observation that JHM.SD infects more cells and expresses more antigen, but produces less infectious virus per cell than A59, implies that efficient replication is not always a correlate of high neurovirulence. This is likely due to the unstable nature of the JHM.SD spike protein (S). JHM.SD induces a generally protective innate immune response; however, the strong neutrophil response may be more pathogenic than protective. In addition, JHM.SD induces only a minimal T-cell response, whereas the strong T-cell response and the concomitant interferon-γ (IFN-γ) induced by the less neurovirulent A59 is protective. Differences in the S and nucleocapsid (N) proteins between A59 and JHM.SD contribute to JHM.SD neuropathogenicity. The hemmagglutinin-esterase (HE) protein may enhance neuropathogenicity of some MHV isolates, but is unlikely a major contributor to the high neuroviruence of JHM.SD. Further data suggest that neither the internal (I) protein nor nonstructural proteins ns4, and ns2 are significant contributors to neurovirulence.
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6076, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Cowley
authors.forename: Susan R
authors.initials: SR
authors.lastname: Weiss
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001921:Brain / Q000276:immunology / Q000821:virology*; D005814:Genes, Viral; D007113:Immunity, Innate; D051379:Mice; D008810:Mice, Inbred C57BL; D006517:Murine hepatitis virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity* / Q000502:physiology; D009474:Neurons / Q000473:pathology* / Q000821:virology*; D019590:Nucleocapsid Proteins / Q000235:genetics / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D014774:Virulence; D014779:Virus Replication
chemical_list: D019590:Nucleocapsid Proteins; D011991:Receptors, Virus