Mutant Murine Hepatitis Virus-Induced Apoptosis in the Hippocampus

The mutant virus Mu-3 was isolated from the soluble receptor-resistant mutant 7 virus (srr7), which is a neuropathogenic strain of the mouse hepatitis virus JHMV, and cloned as a soluble receptor-resistant mutant from the highly neuropathogenic JHMV strain cl-2 virus (cl-2). In order to identify specific characteristcs of Mu-3, the pathology of Mu-3-infected mice was compared with that of srr7- and cl-2-infected mice. The neuropathology after Mu-3 infection exhibited a mixed pattern comparable to that induced by srr7 and cl-2 infections. In addition, Mu-3 infection caused marked apoptotic lesions in the hippocampal region, particularly in the CA2 and CA3 subregions, in the brains of all infected mice. In contrast, in cl-2 infection, 10-20% of the infected mice exhibited apoptosis in the hippocampus, which was primarily observed in the CA1 subregion. Apoptosis also occurred in the pyramidal neurons and CD11b-bearing cells. The apoptotic cells, indicated by caspase 3-activation, were a mixed population of infected and a higher number of uninfected cells. These data indicated that apoptosis observed in Mu-3 infection could be induced by the indirect effects of infection in addition to direct effects of the infected cells occurring in a cell-autonomous manner.