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. 1995 Mar;69(3):1408–1419. doi: 10.1128/jvi.69.3.1408-1419.1995

Induction of focal spongiform neurodegeneration in developmentally resistant mice by implantation of murine retrovirus-infected microglia.

W P Lynch 1, S J Robertson 1, J L Portis 1
PMCID: PMC188727  PMID: 7853473

Abstract

FrCasE is a highly neurovirulent murine leukemia virus which causes a noninflammatory spongiform neurodegenerative disease after neonatal inoculation. The central nervous system (CNS) infection is wide-spread, involving several different cell types, whereas the lesions are localized to motor areas of the brain and spinal cord. Inoculation of FrCasE at 10 days of age (P10) results in viremia, but infection of the CNS is restricted and neurological disease is not observed (M. Czub, S. Czub, F. McAtee, and J. Portis, J. Virol. 65:2539-2544, 1991). In this study, we used this developmental resistance to restrict the extent and the distribution of FrCasE in the brain to examine whether the spongiform degeneration is a consequence of infection of cells in proximity to the lesions. Two approaches were used to infect the brain on or after P10. First, mice were inoculated with FrCasE at P10 to induce viremia and then at P17 were subjected to focal CNS injury within brain regions known to be susceptible to virus-induced spongiform degeneration. The injury resulted in local inflammation, glial activation, migration of inflammatory cells into the wound site, and high-level parenchymal infection about the wound site. However, no evidence of spongiform neurodegeneration was observed over a period of 3 months. The second approach involved the implantation of FrCasE-infected microglia into the CNS at > or = P10. This resulted in microglial engraftment and focal CNS infection unilaterally at the implantation sites and bilaterally along white matter tracts of the corpus callosum and pons and in cells of the subventricular layers of the lateral cerebral ventricles. Strikingly, focal spongiform degeneration colocalized with the sites of infection. In contrast to the wounding experiments, the implantation model was not associated with an inflammatory response or significant glial activation. Results of these studies suggest that (i) the developmental resistance of the CNS to infection lies at the blood-brain barrier and can be bypassed by direct introduction into the brain of virus-infected cells, (ii) the neuropathology induced by this virus is a consequence of local effects of the infection and does not appear to require endothelial or neuronal infection, and (iii) elements of the inflammatory response and/or glial activation may modulate the expression of neuropathology induced by neurovirulent retroviruses.

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Selected References

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