Reovirus Receptors, Cell Entry, and Proapoptotic Signaling

Abstract

Mammalian orthoreoviruses (reoviruses) are members of the Reoviridae. Reoviruses contain 10 double-stranded (ds) RNA gene segments enclosed in two concentric protein shells, called outer capsid and core. These viruses serve as a versatile experimental system for studies of viral replication events at the virus-cell interface, including engagement of cell-surface receptors, internalization and disassembly, and activation of the innate immune response, including NF-κB-dependent cellular signaling pathways. Reoviruses also provide a model system for studies of virus-induced apoptosis and organ-specific disease in vivo. Reoviruses attach to host cells via the filamentous attachment protein, σ1. The σ1 protein of all reovirus serotypes engages junctional adhesion molecule-A (JAM-A), an integral component of intercellular tight junctions. The σ1 protein also binds to cell-surface carbohydrate, with the type of carbohydrate bound varying by serotype. Following attachment to JAM-A and carbohydrate, reovirus internalization is mediated by β1 integrins, most likely via clathrin-dependent endocytosis. In the endocytic compartment, reovirus outer-capsid protein σ3 is removed by acid-dependent cysteine proteases in most cell types. Removal of σ3 results in the exposure of a hydrophobic conformer of the viral membrane-penetration protein, μ1, which pierces the endosomal membrane and delivers transcriptionally active reovirus core particles into the cytoplasm. Reoviruses induce apoptosis in both cultured cells and infected mice. Perturbation of reovirus disassembly using inhibitors of endosomal acidification or protease activity abrogates apoptosis. The μ1-encoding M2 gene is genetically linked to strain-specific differences in apoptosis-inducing capacity, suggesting a function for μ1 in induction of death signaling. Reovirus disassembly leads to activation of transcription factor NF-κB, which modulates apoptotic signaling in numerous types of cells. Inhibition of NF-κB nuclear translocation using either pharmacologic agents or expression of transdominant forms of IκB blocks reovirus-induced apoptosis, suggesting an essential role for NF-κB activation in the death response. Multiple effector pathways downstream of NF-κB directed gene expression execute reovirus-induced cell death. This chapter will focus on the mechanisms by which reovirus attachment and disassembly activate NF-κB and stimulate the cellular proapoptotic machinery.

A Phase I Trial of Single-Agent Reolysin in Patients with Relapsed Multiple Myeloma

“…Once attached, ß1-integrin mediated viral internalization occurs via clathrin dependent endocytosis. Following internalization, acid-dependent cysteine proteases in the endocytic compartment remove the outer capsid protein σ3, exposing a viral membrane-penetration protein that is responsible for piercing the endosomal membrane and delivering transcriptionally active virus into the cytoplasm (23). …”

Reovirus intermediate subviral particles constitute a strategy to infect intestinal epithelial cells by exploiting TGF-β dependent pro-survival signaling

“…Mammalian reovirus (MRV) is the prototypic member of the Orthoreoviridae family. MRV is a double stranded RNA virus made up of 10 segments, which encode for 12 proteins (Danthi et al ., ; Chandran & Nibert, ). The MRV capsid consists of a double‐layered protein shell, which is shed in sequential steps during the entry of the virus particle (Danthi et al ., ; Chandran & Nibert, ).…”

Viral gene expression potentiates reovirus-induced necrosis

“…Mammalian reovirus, henceforth referred to as reovirus, is used as an experimental system to understand how the interplay between viral and cellular factors controls the induction and execution of death responses (Danthi, 2013). One form of programmed cell death, apoptosis, contributes to encephalitis and myocarditis following reovirus infection of cells within the central nervous system and heart, respectively (Beckham et al, 2010; Berens and Tyler, 2011; Danthi et al, 2008a; Danthi et al, 2008b; Danthi et al, 2010; DeBiasi et al, 2004; O'Donnell et al, 2005; Richardson-Burns et al, 2002).…”