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

Abstract

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 apoptotis and necroptosis restored virus yields.

Opposite Effects of Apoptotic and Necroptotic Cellular Pathways on Rotavirus Replication

“…In the present study, inhibition of apoptosis using the pan-caspase inhibitor (Z-VAD-FMK) increased RVA replication, indicating that RVA-induced apoptosis is a host defense mechanism. This result is in agreement with the findings of studies in which the inhibition of TMEV- and HIV-1-induced apoptosis of infected murine macrophages and CD4 T lymphocytes, respectively, induced a transition from apoptosis to necroptosis and resulted in significantly higher viral titers ( 49 , 50 ). Taken together, our data suggest that the RVA-induced RIPK1-dependent pathway acts as a proviral mechanism that promotes viral replication and/or spread, whereas—consistent with the findings of a previous study ( 56 )—RVA-induced apoptosis is an antiviral strategy that restricts viral replication.…”

“…The transition from apoptosis to necroptosis and vice versa has been reported in response to HIV-1 infection, Theiler’s murine encephalomyelitis virus (TMEV) infection, and tunicamycin stimulation ( 49 , 50 , 57 ). Our results suggested that the decrease in RVA titers in response to the downregulation of the necroptosis molecules, RIPK1, RIPK3, and MLKL, could be attributed to protection from cell death, induction of apoptosis, or both mechanisms.…”

“…Although necroptosis and apoptosis are generally considered antiviral mechanisms, they are also considered beneficial to the virus in some cases, as they may promote viral release and spread ( 44 , 49 , 50 , 54 , 55 ). In this study, we used chemical inhibitors specific for each key molecule involved in RIPK1-dependent necroptosis to determine the role of necroptosis in RVA replication.…”

Receptor interacting protein 3-induced RGC-5 cell necroptosis following oxygen glucose deprivation

“…Zhang et al examined TNF-induced necrosis in NIH 3T3 cells and showed that RIP3 regulates TNF-induced ROS overproduction by activating metabolic enzymes, leading to necrosis via damaging of cellular membranes and organelles [ 12 ]. Son et al [ 13 ] showed that Nec-1 can significantly reduce ROS production in Theiler’s murine encephalomyelitis virus (TMEV)-infected macrophages. Our previous studies showed that Timosaponin B-II, an anti-oxidative monomer extracted from Rhizoma anemarrhenae , reduced retinal ganglion cell-5 (RGC-5) cell necroptosis by inhibiting ROS accumulation [ 14 ].…”

Therapeutic targeting of liver cancer with a recombinant DNA vaccine containing the hemagglutinin-neuraminidase gene of Newcastle disease virus via apoptotic-dependent pathways

“…In addition, apoptosis may be regulated at the genetic level due to the expression of certain viral proteins or the triggering of novel genes (28,29). In recent years, specifically infecting tumor cells with viruses to induce apoptosis became an important aspect of cancer biotherapy, thus further manipulating tumor development (18,30).…”