Mechanisms of Primary Axonal Damage in a Viral Model of Multiple Sclerosis

• Published in: The Journal of neuroscience Vol. 29; no. 33; pp. 10272 - 10280
• Main Authors: Das Sarma, Jayasri, Kenyon, Lawrence C, Hingley, Susan T, Shindler, Kenneth S
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 19-08-2009; Society for Neuroscience
• Subjects: Animals; Axons - metabolism; Axons - pathology; Axons - virology; Cells, Cultured; Disease Models, Animal; Inflammation Mediators - metabolism; Mice; Mice, Inbred C57BL; Multiple Sclerosis - metabolism; Multiple Sclerosis - pathology; Multiple Sclerosis - virology; Murine hepatitis virus - genetics; Murine hepatitis virus - pathogenicity; Myelin Sheath - metabolism; Myelin Sheath - pathology; Myelin Sheath - virology; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Nerve Degeneration - virology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1975-09.2009

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Recent studies have demonstrated that significant axonal injury also occurs in MS patients and correlates with neurological dysfunction, but it is not known whether this neuronal damage is a primary disease process, or occurs only secondary to demyelination. In the current studies, neurotropic strains of mouse hepatitis virus (MHV) that induce meningitis, encephalitis, and demyelination in the CNS, an animal model of MS, were used to evaluate mechanisms of axonal injury. The pathogenic properties of genetically engineered isogenic spike protein recombinant demyelinating and nondemyelinating strains of MHV were compared. Studies demonstrate that a demyelinating strain of MHV causes concomitant axonal loss and macrophage-mediated demyelination. The mechanism of axonal loss and demyelination in MHV infection is dependent on successful transport of virus from gray matter to white matter using the MHV host attachment spike glycoprotein. Our data show that axonal loss and demyelination can be independent direct viral cytopathic events, and suggest that similar direct axonal damage may occur in MS. These results have important implications for the design of neuroprotective strategies for CNS demyelinating disease, and our model identifies the spike protein as a therapeutic target to prevent axonal transport of neurotropic viruses.