THEILERS VIRUS GROWTH IN MURINE MACROPHAGE CELL-LINES DEPENDS ON THE STATE OF DIFFERENTIATION

Theiler's murine encephalomyelitic virus (TMEV) preferentially replica tes in macrophages in the central nervous system of mice during the pe rsistent phase of infection. Macrophages accumulate in demyelinating l esions and are evidently the primary cell to harbor virus. To investig ate TMEV-macrophage interactions, we studied GDVII infection of three cell lines, Mf, P388D1, and RAW264.7, representing Various stages of m acrophage differentiation/activation. GDVII virus was bound and intern alized by RAW264.7 and P388D1 cells, but not by the precursor cell lin e M1. While infection of P388D1 cells produced a typical lytic cytopat hology with marked loss of cellular activity to 10-20% of the uninfect ed control cells, RAW264.7 cells showed little cytopathology despite a decrease in cellular activity of 50-60%. Morphologic changes in infec ted RAW264.7 cells were similar to those occurring after cell activati on. Although an infectious center assay showed that all P388D1 and RAW 264.7 cells were infected, synthesis of viral RNA and proteins was mar kedly reduced and virus titers were restricted compared to permissive BHK-21 cells. Infected RAW264.7, but not infected P388D1, cells secret ed tumor necrosis factor-alpha 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 s ecrete cytokines (P388D1). (C) 1995 Academic Press, Inc.