FIG. 9.

Pathways of Fr98, EC, and BE virus-mediated neurovirulence. Solid arrows indicate results from the present study. Broken arrows are hypothesized pathways that have not been demonstrated. Fr98 encodes both the EC and BE virus neurovirulence determinants and may use both pathways to mediate neurovirulence. EC virus-mediated disease requires TNF-α (Fig. 4B), which is also necessary for EC virus-induced microglia activation (Fig. 7). EC virus-induced astrocyte activation was not dependent on TNF-α (Fig. 7), and the activation of astrocytes in nonsymptomatic EC virus-infected TNF-α^−/− mice indicates that astrocyte activation alone is not sufficient for disease induction. BE virus-induced neurovirulence did not require either TNF-α (Fig. 4A) or microglia and/or macrophage activation (Fig. 8). Thus, BE virus appears to mediate disease through other pathways, possibly through astrocyte production of MCP-1, as suggested in a previous report (24).