Mechanisms of Reovirus-Induced Cell Death and Tissue Injury: Role of Apoptosis and Virus-Induced Perturbation of Host-Cell Signaling and Transcription Factor Activation

Abstract

Reoviruses have provided insight into the roles played by specific viral genes and the proteins they encode in virus-induced cell death and tissue injury. Apoptosis is a major mechanism of cell death induced by reoviruses. Reovirus-induced apoptosis involves both death-receptor and mitochondrial cell death pathways. Reovirus infection is associated with selective activation of mitogen activated protein kinase (MAPK) cascades including JNK/SAPK. Infection also perturbs transcription factor signaling resulting in the activation of c-Jun and initial activation followed by strain-specific inhibition of NF-κB. Infection results in changes in the expression of genes encoding proteins involved in cell cycle regulation, apoptosis, and DNA damage and repair processes. Apoptosis is a major mechanism of reovirus-induced injury to key target organs including the CNS and heart. Inhibition of apoptosis through the use of caspase or calpain inhibitors, minocycline, or in caspase 3 −/− mice all reduce virus-associated tissue injury and enhance survival of infected animals. Reoviruses induce apoptotic cell death (oncolysis) in a wide variety of cancer cells and tumors. The capacity of reoviruses to grow efficiently in transformed cells is enhanced by the presence of an activated Ras signaling pathway likely through mechanisms involving inhibition of antiviral PKR signaling and activation of Ras/RalGEF/p38 pathways. The potential of reovirus-induced oncolysis in therapy of human cancers is currently being investigated in phase I/II clinical trials.

B‐cell‐activating factor expressions in salivary epithelial cells after dsRNA virus infection depends on RNA‐activated protein kinase activation

“…Interestingly, activation of a human T-cell line with 12-O-tetradecanoylphorbol-13-acetate and ionomycin induces BAFF expression through a signal transduction pathway involving p38 MAPK [23]. Some reports have previously shown that the activation of p38 MAPK depends on the serotype of reovirus and the type of cell infected [24][25][26]. Indeed, the serotype used in this study was the T1 serotype 1 prototype strain Lang, which is known not to activate p38 MAPK [24].…”

Transient infection of freshly isolated human colorectal tumor cells by reovirus T3D intermediate subviral particles

“…Reovirus T3D is an oncolytic virus that kills susceptible cells by inducing apoptosis. 4 We have recently shown that oncogenic KRAS sensitizes human and mouse colorectal tumor cells to apoptosis induction by reovirus T3D. 5,6 Alternatively, KRAS may facilitate virus replication.…”

KRASD13 Promotes Apoptosis of Human Colorectal Tumor Cells by ReovirusT3D and Oxaliplatin but not by Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand

“…However, we have recently shown that suppression of endogenous KRAS D12 in mouse colorectal carcinoma cells had no effect on reovirus protein synthesis or on virus replication but abrogated ReovirusT3D-induced tumor cell apoptosis (6). Activation of the apoptotic program in virus-infected cells is a natural defense mechanism that limits viral spread in the infected host (7). Alternatively, apoptosis of infected cells may facilitate the release of virus progeny and subsequent dissemination (7).…”

“…Activation of the apoptotic program in virus-infected cells is a natural defense mechanism that limits viral spread in the infected host (7). Alternatively, apoptosis of infected cells may facilitate the release of virus progeny and subsequent dissemination (7). From a therapeutic point of view, the apoptosis-inducing strains of reovirus may be regarded as self-amplifying inducers of tumor cell apoptosis with limited pathogenic side effects.…”