Abstract
Demyelination in the central nervous system induced by neurovirulent strains of Mouse Hepatitis Virus (MHV) is mediated by the viral spike glycoprotein, but it is not clear whether the mechanism of this disease pathology involves direct viral infection of oligodendrocytes. Detailed studies of glial cell tropism of MHV are presented, demonstrating that direct MHV infection of oligodendrocytes differs between demyelinating (RSA59) and non-demyelinating (RSMHV2) viral strains both in vitro and in vivo. Our results indicate that direct injury of mature oligodendrocytes is an important mechanism of virus-induced demyelination. In vivo, RSA59 infection was identified in spinal cord gray and white matter, but infected oligodendrocytes were restricted to white matter. In contrast, RSMHV2 infection was restricted to gray matter neurons and was not localized to oligodendrocytes. In vitro, RSA59 can infect both oligodendrocyte precursors and differentiated oligodendrocytes, whereas RSMHV2 can infect oligodendrocyte precursors but not differentiated oligodendrocytes. Viral spreading through axonal means to white matter and release of the demyelinating strain MHV at the nerve end is critical for oligodendrocytes infection and subsequent demyelination. Understanding the mechanisms by which known viruses effect demyelination in this animal model has important therapeutic implications in the treatment of human demyelinating disease.
Highlights
Demyelination is the process by which axons lose their normal insulating myelin
While at day 5 post-infection, the RSMHV2 strain viral antigen is transported to the spinal cord from the brain, viral replication and spread is primarily confined within the gray matter even at day 7 post-infection with infrequent spread to the white matter
Axonal damage can occur concurrently with and independently of demyelination and direct viral-mediated axonal damage can occur as a primary pathology, separate from demyelination
Summary
Demyelination is the process by which axons lose their normal insulating myelin. Multiple sclerosis (MS) is a chronic, progressive, or relapsing and remitting demyelinating disorder that affects the central nervous system (CNS) . The mechanism of demyelination in MS is unknown, but may involve a T cell response triggered by virus infection (Allen and Brankin, 1993; Hernán et al, 2001; Hemmer et al, 2002). Mouse Hepatitis Virus Induced Gliopathy attempts to identify an etiologic agent, a specific virus has not been recognized. Various animal models have been developed to study MS, including experimental autoimmune encephalomyelitis (Kornek et al, 2000) as well as viral-induced CNS demyelinating disease models. One useful mouse model utilizes MHV-induced demyelination that mimics the pathology of MS (Das Sarma, 2010)
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