The murine coronavirus, mouse hepatitis virus (MHV) causes acute encephalitis and, followed by a chronic demyelinating disease in mice;the latter is a recognized animal model for the study of human demyelinating diseases, such as multiple sclerosis. The extent of neurovirulence induced by MHV is dependent on both viral and host factors;viral strains differ in virulence and tropism and multiple viral genes contribute to the extent of virulence. We have used chimeric recombinant viruses with genes derived from the highly neurotropic JHM strain and the less neurotropic A59 strain to carry out studies, in the mouse model, of the viral determinants of neurovirulence. These studies have shown that the spike protein, the mediator of viral attachment and spread, is clearly a major contributor to neurovirulence;however, it is also clear that other viral genes play important roles in determining the extent of neurovirulence. We test here the hypothesis that other structural genes as well as non-structural genes contribute to neurovirulence. We propose to construct an infectious cDNA clone from the JHM strain of MHV;we will then use this cDNA along with an existing A59 full length cDNA to recover chimeric viruses with defined crossover points. We will use these viruses to determine the importance of structural versus nonstructural genes in neurovirulence. We will then focus on the roles of two non essential proteins, hemagglutinin esterase (HE) and the ORF 2a encoded 30 kDa protein in neurovirulence;there are preliminary data indicating that both of these proteins do influence virulence, likely by different mechanisms. The HE protein is expressed by the highly neurovirulent JHM strain but not the A59 strain. We will continue ongoing studies indicating that expression of HE does indeed increase virulence in the central nervous system and begin to address the mechanism of this enhancement. The 30kDa protein encoded in ORF2a is specific to group 2 coronaviruses;we have recently observed that one amino acid substitution within this protein results in attenuation of recombinant MHV-A59. We will pursue these findings by investigating the pathogenesis of viruses in which expression of ORF2a has been eliminated or its gene product mutated. The focus will be on a role for the ORF2a protein in enhancing neurovirulence, possibly through interacting with the host immune response. We believe these studies will lead to a better understanding of the determinants of neurovirulence during MHV infection.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Wong, May
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University of Pennsylvania
Schools of Medicine
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