Inhibition of Theiler's virus-induced apoptosis in infected murine macrophages results in necroptosis

•Theiler's virus induces apoptosis in murine macrophages through the intrinsic pathway reducing virus yields late in infection.•Inhibition of apoptosis led to the induction of necroptosis, a programmed form of necrosis.•Signaling events preceding necroptosis included phosphorylation of receptor interacting protein 1 (RIP1) and localization of RIP1 and RIP3 to mitochondria.•Blocking both apoptosis and necroptosis restored virus yields. In mice Theiler's murine encephalomyelitis virus (TMEV) persists in macrophages that eventually undergo apoptosis. TMEV infection of macrophages in culture induces apoptosis through the intrinsic pathway, restricting virus yields. We show that inhibition of TMEV-induced apoptosis leads to phosphorylation of receptor interacting protein 1 (RIP1), localization of RIP1 and RIP3 to mitochondria, ROS production independent of MAPK activation and programmed necrosis (necroptosis). Blocking both apoptosis and necroptosis restored virus yields.