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

Abstract

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.

Macrophage-Mediated Optic Neuritis Induced by Retrograde Axonal Transport of Spike Gene Recombinant Mouse Hepatitis Virus

“…As in prior studies, RSA59-infected mice showed meningitis, encephalitis, myelitis and concurrent axonal loss and demyelination as early as day 5 pi with an increase at day 30, whereas RSMHV2 showed only meningitis, encephalitis and myelitis with no significant demyelination or axonal loss (data not shown) (2). The livers of both strains showed moderate to severe hepatitis (data not shown), thereby confirming virulence.…”

“…There is a lack of viral antigen spread and subsequent inflammation extending into spinal cord white matter following intracranial infection with the NDM strain, whereas there is extensive macrophage-mediated white matter pathology secondary to DM strain infection. Thus, the spike protein plays a critical role in anterograde axonal transport of viral particles, an important mechanism mediating axonal damage and demyelination (2, 4). Because both strains cause encephalitis following transcranial inoculation, the differences in spike protein between DM and NDM strains do not impair viral entry; however, differential neural cell tropism may contribute to the mechanism of demyelination (2, 4, 5).…”

“…Thus, the spike protein plays a critical role in anterograde axonal transport of viral particles, an important mechanism mediating axonal damage and demyelination (2, 4). Because both strains cause encephalitis following transcranial inoculation, the differences in spike protein between DM and NDM strains do not impair viral entry; however, differential neural cell tropism may contribute to the mechanism of demyelination (2, 4, 5). Infection of brain neurons and oligodendrocytes occurs upon inoculation with either strain, whereas in the spinal cord, oligodendrocyte infection is only seen with the DM strain.…”

Steroids Impact on Myelin Repair, Neurogenesis and Visual Pathway in Multiple Sclerosis: Preclinical Perspectives

“…Accumulating evidence on experimental virus-induced ON and transgenic models of the axonal/demyelinating disease and EAE suggest that various etiopathogenic mechanisms can trigger MS-and/or ON-like disease in rodents [34][35][36]. Axonal loss/dysfunction can occur because of a variety of nonviral causes: most notably, neurotoxins and associated downstream or intermediary products, including free radicals/oxidative damage, risk genes, and an array of other predisposing elements such as channel abnormalities/calcium elevations-all of which can lead to destruction of neurons [37][38][39] and contribute to lesions pathogenesis in multiple sclerosis [40][41][42].…”

SHP-1–Dependent Macrophage Differentiation Exacerbates Virus-Induced Myositis

“…As a consequence of these infections, spreading of the virus from muscle to CNS by retrograde axonal transport or viremia may occur causing severe neuropathological complications (16–20). Skeletal muscle is therefore a clinically significant target of virus infections in humans and the mechanisms involved in this process must be further elucidated.…”