Theiler's murine encephalomyelitis virus induces rapid necrosis and delayed apoptosis in myelinated mouse cerebellar explant cultures

Infection with the Daniel strain of Theiler's murine encephalomyelitis (TME V-DA) virus induces persistent demyelinating lesions in mice and serves as a model for multiple sclerosis. During the acute phase of the disease, howe ver, viral infection leads to cell death in vivo. Viral-induced death may r esult directly from viral infection of neural cells, or indirectly, by acti vation of the immune system. To examine the direct effects of TMEV infectio n on neural cells, myelinated explant cultures of the murine cerebellum wer e infected with 10(5) pfu of TMEV-DA for periods ranging from 1 to 72 h. Ou r results indicate that TMEV-DA replicates in cultured neural tissue. Initi ally, viral antigen is localized to a few isolated neural cells. However, w ithin 72 h antigen was observed in multiple fuci that included damaged cell s and extracellular debris. Viral infection led to a rapid and cyclical ind uction of necrosis with a time period that was consistent with the lytic ph ase of the viral life-cycle. Simultaneously, we observed an increase in apo ptosis 48 h post-infection. Electron micrographic analysis indicated that v iral-infected cultures contained cells with fragmented nuclei and condensed cytoplasm, characteristic of apoptosis. The localization of apoptosis to t he cerebellar granule cell layer, identified these cells as presumptive gra nule neurons. Viral infection, however, did not lead to myelin damage, thou gh damaged axons were visible in TMEV-infected cultures. These results sugg est that during the acute phase of infection, TMEV targets neural cells for apoptosis without directly disrupting myelin. Myelin damage may therefore result from the activation of the immune system. (C) 2000 Elsevier Science B.V. All rights reserved.