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Mouse Viral Studies Provide CNS Disease Insights

Several types of virus, including the Theiler murine encephalitis virus, can trigger in mice a disease that very much resembles multiple sclerosis (MS) in humans, according to Robert Fujinami of the University of Utah in Salt Lake City, another participant during the symposium, "RNA Neurovirology/Gene Delivery to the CNS." No single type of virus but a "host of viruses" likely provide the immunologic stimuli that lead to MS in humans, he says.

The highly neurovirulent strain of this picornavirus is capable of causing an acute form of encephalitis in mice, attacking neurons directly and triggering massive apoptosis, or cell death, within the brain and rapidly killing susceptible animals within about a week of onset, Fujinami says. Mice survive an infection with a less neurovirulent strain of Theiler's virus, but develop an inflammatory response leading to demyelination within the central nervous system (CNS)—the cardinal pathologic sign of MS in humans.

Survival rates are higher in animals infected with various less-virulent strains of the virus, which tend to infect glial cells rather than neurons in the CNS, according to Fujinami. This shift in target cells for the virus is due, in part, to minor changes in viral structural proteins, presumably enabling them to bind to an alternative cell surface receptor. The less-virulent strains also trigger a localized inflammatory response that leads to demyelination, and thus many of the symptomatic responses that typify MS in humans, he says.

These inflammatory responses appear to be immune mediated, involve CD8 T cells and oligodendrocytes, and are accompanied by locally increased levels of immune mediator molecules, including several interleukins and interferon-gamma, according to Fujinami. As part of this suite of responses, neighboring uninfected cells within the CNS of mice are being killed. Such killing "requires cell-cell contact," involves CD8 rather than natural killer cells, and depends on viral capsid proteins, which apparently activate the CD8 cells, he says.

Treating mice with naked DNA molecules also enhances these pathologic responses within the CNS of mice, providing something of a "caveat" about using vaccines that consist of such molecules, Fujinami continues. "Just priming with plasmid DNA can increase the amount of disease," he says. "If we take plasmids encoding viral proteins, we can potentiate disease or diminish it, depending on the viral genes."