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Reovirus Receptors, Cell Entry, and Proapoptotic Signaling

  • Chapter
Viral Entry into Host Cells

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 790))

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 pathway s 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.

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Authors and Affiliations

  1. Department of Biology, Indiana University, Bloomington, Indiana, USA

    Pranav Danthi

  2. Department of Biology, Colgate University, Hamilton, New York, USA

    Geoffrey H. Holm

  3. Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

    Thilo Stehle & Terence S. Dermody

  4. Interfakultäres Institut für Biochemie, Eberhard-Karls Universität, Tübingen, Germany

    Thilo Stehle

  5. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

    Terence S. Dermody

  6. Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

    Terence S. Dermody

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  1. Pranav Danthi
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  2. Geoffrey H. Holm
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  3. Thilo Stehle
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  4. Terence S. Dermody
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Correspondence to Terence S. Dermody .

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Editors and Affiliations

  1. Institute for Virology, Hannover Medical School, Hannover, Germany

    Stefan Pöhlmann PhD

  2. German Primate Center, Göttingen, Germany

    Stefan Pöhlmann PhD

  3. Blood Systems Research Institute, and Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA

    Graham Simmons PhD

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Danthi, P., Holm, G.H., Stehle, T., Dermody, T.S. (2013). Reovirus Receptors, Cell Entry, and Proapoptotic Signaling. In: Pöhlmann, S., Simmons, G. (eds) Viral Entry into Host Cells. Advances in Experimental Medicine and Biology, vol 790. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7651-1_3

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