Indirect evidence implicates a virus in the etiology of Multiple Sclerosis (MS) and more direct evidence shows that viruses cause other human demyelinating diseases. Coronavirus mouse hepatitis virus (MHV) infection of mice is a good model system for the study of virus-induced chronic demyelination. The long term goal of this project is to use the techniques of molecular biology to understand the mechanisms of persistent infection and virus-induced chronic CNS disease in this animal model. We have previously shown that intracerebral inoculation of MHV-A59 into 4-6 week old C57BL/6 mice results in chronic CNS disease in 100% of the animals with very little acute disease or mortality. Primary demyelination can be detected as late as six months post infection and can be enhanced by immunosuppression. While infectious virus and viral antigens cannot be detected during the chronic disease state, viral nucleic acids do persist. In this proposal we will study the mechanism of viral persistence and its relationship to demyelination. Using in situ hybridization and gene-specific cloned MHV-A59 cDNAs as probes to detect viral nucleic acids and immunoperoxidase staining with antisera directed against individual viral proteins we will determine if part or all of the viral genome is expressed at the transcriptional and translational levels. Cyclophosphamide treatment will be carried out to determine if virus can be recovered from chronically infected animals that have been immunosuppressed. Viral tropism will be studied by carrying out infections in vitro in enriched oligodendrocyte cultures. As a more secondary goal we will investigate the possible relationship between human coronaviruses and MS. We will use the highly specific and sensitive technique of nucleic acid hybridization to probe for coronavirus sequences in the CNS of MS patients. Thus, in situ hybridization of CNS autopsy tissue from MS patients will be carried out using cloned DNA fragments homologous to human coronavirus genomes as probes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS021954-01
Application #
3403701
Study Section
Virology Study Section (VR)
Project Start
1985-07-01
Project End
1990-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Navas-Martin, Sonia; Brom, Maarten; Chua, Ming-Ming et al. (2007) Replicase genes of murine coronavirus strains A59 and JHM are interchangeable: differences in pathogenesis map to the 3'one-third of the genome. J Virol 81:1022-6
Weiss, Susan R; Navas-Martin, Sonia (2005) Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus. Microbiol Mol Biol Rev 69:635-64
Navas-Martin, Sonia; Hingley, Susan T; Weiss, Susan R (2005) Murine coronavirus evolution in vivo: functional compensation of a detrimental amino acid substitution in the receptor binding domain of the spike glycoprotein. J Virol 79:7629-40
Navas-Martin, Sonia R; Weiss, Susan (2004) Coronavirus replication and pathogenesis: Implications for the recent outbreak of severe acute respiratory syndrome (SARS), and the challenge for vaccine development. J Neurovirol 10:75-85
Navas, Sonia; Weiss, Susan R (2003) Murine coronavirus-induced hepatitis: JHM genetic background eliminates A59 spike-determined hepatotropism. J Virol 77:4972-8
Tsai, Jean C; de Groot, Linda; Pinon, Josefina D et al. (2003) Amino acid substitutions within the heptad repeat domain 1 of murine coronavirus spike protein restrict viral antigen spread in the central nervous system. Virology 312:369-80
Zelus, Bruce D; Schickli, Jeanne H; Blau, Dianna M et al. (2003) Conformational changes in the spike glycoprotein of murine coronavirus are induced at 37 degrees C either by soluble murine CEACAM1 receptors or by pH 8. J Virol 77:830-40
Tsai, Jean C; Zelus, Bruce D; Holmes, Kathryn V et al. (2003) The N-terminal domain of the murine coronavirus spike glycoprotein determines the CEACAM1 receptor specificity of the virus strain. J Virol 77:841-50
Navas-Martin, Sonia; Weiss, Susan R (2003) SARS: lessons learned from other coronaviruses. Viral Immunol 16:461-74
Das Sarma, Jayasri; Scheen, Esther; Seo, Su-Hun et al. (2002) Enhanced green fluorescent protein expression may be used to monitor murine coronavirus spread in vitro and in the mouse central nervous system. J Neurovirol 8:381-91

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