title: The murine coronavirus nucleocapsid gene is a determinant of virulence.
abstract: The murine coronavirus, mouse hepatitis virus (MHV) strain A59, causes acute encephalitis and chronic demyelinating disease as well as hepatitis in mice. The JHM strain (also called MHV-4 or JHM.SD) causes fatal encephalitis and only minimal hepatitis. Previous analysis of chimeric recombinant MHVs in which the spike gene, encoding the protein that mediates viral entry and cell-to-cell fusion, was exchanged between JHM and A59 showed that the spike plays a major role in determining organ tropism and neurovirulence but that other genes also play important roles in pathogenic outcome. Here, we have investigated the role of the nucleocapsid protein in MHV-induced disease. The multifunctional nucleocapsid protein is complexed with the genomic RNA, interacts with the viral membrane protein during virion assembly, and plays an import role in enhancing the efficiency of transcription. A pair of chimeric recombinant viruses in which the nucleocapsid gene was exchanged between JHM and A59 was selected and compared to wild-type parental strains in terms of virulence. Importantly, expression of the JHM nucleocapsid in the context of the A59 genome conferred increased mortality and spread of viral antigen in the mouse central nervous system compared to the parental A59 strain, while having little effect on the induction of hepatitis. While the JHM nucleocapsid did not appear to enhance neuron-to-neuron spread in primary neuronal cultures, the increased neurovirulence it conferred may be due in part to the induction of a less robust T-cell response than that induced by strain A59.
authors.affiliation: Department of Microbiology, University of Pennsylvania, School of Medicine, 36th Street and Hamilton Walk, Philadelphia, PA 19104-6076, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Cowley
authors.forename: Simon Y
authors.initials: SY
authors.lastname: Long
authors.forename: Susan R
authors.initials: SR
authors.lastname: Weiss
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000378:metabolism; D001921:Brain / Q000276:immunology / Q000473:pathology / Q000821:virology; D002415:Cats; D002478:Cells, Cultured; D018352:Coronavirus Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D000086462:Coronavirus Nucleocapsid Proteins; D005814:Genes, Viral; D016679:Genome, Viral; D006524:Hepatitis, Viral, Animal / Q000276:immunology / Q000473:pathology / Q000821:virology; D008099:Liver / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D006517:Murine hepatitis virus / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D009474:Neurons / Q000821:virology; D019590:Nucleocapsid Proteins / Q000235:genetics* / Q000276:immunology; D011995:Recombination, Genetic; D013601:T-Lymphocytes / Q000276:immunology; D014774:Virulence / Q000235:genetics; D019065:Virus Assembly; D014779:Virus Replication
chemical_list: D000956:Antigens, Viral; D000086462:Coronavirus Nucleocapsid Proteins; D019590:Nucleocapsid Proteins