The Role of Myelin in Theiler's Virus Persistence in the Central Nervous System

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Abstract
Theiler's virus, a picornavirus, persists for life in the central nervous system of mouse and causes a demyelinating disease that is a model for multiple sclerosis. The virus infects neurons first but persists in white matter glial cells, mainly oligodendrocytes and macrophages. The mechanism, by which the virus traffics from neurons to glial cells, and the respective roles of oligodendrocytes and macrophages in persistence are poorly understood. We took advantage of our previous finding that the shiverer mouse, a mutant with a deletion in the myelin basic protein gene (Mbp), is resistant to persistent infection to examine the role of myelin in persistence. Using immune chimeras, we show that resistance is not mediated by immune responses or by an efficient recruitment of inflammatory cells into the central nervous system. With both in vivo and in vitro experiments, we show that the mutation does not impair the permissiveness of neurons, oligodendrocytes, and macrophages to the virus. We demonstrate that viral antigens are present in cytoplasmic channels of myelin during persistent infection of wild-type mice. Using the optic nerve as a model, we show that the virus traffics from the axons of retinal ganglion cells to the cytoplasmic channels of myelin, and that this traffic is impaired by the shiverer mutation. These results uncover an unsuspected axon to myelin traffic of Theiler's virus and the essential role played by the infection of myelin/oligodendrocyte in persistence. Theiler's virus persists in the central nervous system of mice and causes a chronic disease that resembles multiple sclerosis, a common demyelinating disease of humans. The virus infects neurons for one to two weeks, but later on it persists in the white matter, in oligodendrocytes and also in macrophages. Oligodendrocytes are the myelin-making cells of the central nervous system. Strikingly, in mice with a genetic defect of myelin, the virus infects neurons normally but is unable to persist. Understanding the reason for the lack of persistence in this mutant mouse should pinpoint an essential step in the complex process resulting in persistence. In this article, we show that resistance to persistent infection is not mediated by the immune system and is not due to inefficient viral replication in oligodendrocytes or macrophages. Instead, we show that virus transported in axons traffics into the myelin, and that this traffic is interrupted by the myelin mutation. This unsuspected axon to myelin traffic of Theiler's virus is necessary for viral persistence. Our results warrant looking for a similar phenomenon in other persistent infections of the nervous system, including in humans.