Theiler's Virus Growth in Murine Macrophage Cell Lines Depends on the State of Differentiation

Theiler's murine encephalomyelitic virus (TMEV) preferentially replicates in macrophages in the central nervous system of mice during the persistent phase of infection. Macrophages accumulate in demyelinating lesions and are evidently the primary cell to harbor virus. To investigate TMEV-macrophage interactions, we studied GDVII infection of three cell lines, M1, P388D1, and RAW264.7, representing various stages of macrophage differentiation/activation. GDVII virus was bound and internalized by RAW264.7 and P388D1 cells, but not by the precursor cell line M1. While infection of P388D1 cells produced a typical lyric cytopathology with marked loss of cellular activity to 10-20% of the uninfected control cells, RAW264.7 cells showed little cytopathology despite a decrease in cellular activity of 50-60%. Morphologic changes in infected RAW264.7 cells were similar to those occurring after cell activation. Although an infectious center assay showed that all P388D1 and RAW264.7 cells were infected, synthesis of viral RNA and proteins was markedly reduced and virus titers were restricted compared to permissive BHK-21 cells. Infected RAW264.7, but not infected P388D1, cells secreted tumor necrosis factor-α and nitric oxide. Therefore, depending on the differentiation and/or activation state, murine macrophages may be resistant to TMEV infection (M1), semipermissive and activated to secrete cytokines (RAW264.7), or semipermissive and not activated to secrete cytokines (P388D1).