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.
Highlights
The mechanisms by which viruses escape immune detection and establish persistent infections are extremely diverse
We describe how the infection of myelin and oligodendrocytes by virions transported in the axons of infected neurons is a critical step in the establishment of a persistent infection of the central nervous system (CNS) by Theiler’s murine encephalomyelitis virus (TMEV)
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
Summary
The mechanisms by which viruses escape immune detection and establish persistent infections are extremely diverse. Once in the CNS, the virus causes an acute encephalomyelitis with infection of neurons, and to a lesser extent, of macrophages and astrocytes in gray matter [2]. This ‘‘early disease’’ lasts approximately 2 wk, after which the virus is either cleared by the immune response, or persists in the CNS if the animals are genetically susceptible. The virus does not persist in neurons but in glial cells of the white matter of spinal cord, mainly macrophage/microglial cells and oligodendrocytes, the myelin-making cells, and to a lesser extent astrocytes [4,5]. The infection by TMEV of genetically susceptible mouse strains, such as the SJL/J and C3H strains, is a classical MS model [1]
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