The Reovirus σ1s Protein Is a Determinant of Hematogenous but Not Neural Virus Dissemination in Mice

Boehme, Karl W.; Frierson, Johnna M.; Konopka, Jennifer L.; Kobayashi, Takeshi; Dermody, Terence S.

doi:10.1128/jvi.02289-10

Cited by 37 publications

(74 citation statements)

References 46 publications

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“…Our results do not suggest a role for apoptotic capacity in viral dissemination in the host. Of note, another study from our laboratory indicates that the nonstructural protein 1s is required for full apoptotic potential in cultured cells and bloodstream dissemination in mice following intramuscular inoculation (54). This finding suggests that different viral determinants are relatively more important for apoptosis induction in different tissues.…”

Section: Discussionmentioning

confidence: 75%

Apoptosis Induction Influences Reovirus Replication and Virulence in Newborn Mice

Pruijssers

Hengel

Abel

et al. 2013

J Virol

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Apoptosis is a type of controlled cell death that is essential for development and tissue homeostasis. It also serves as a robust host response against infection by many viruses. The capacity of neurotropic viruses to induce apoptosis strongly correlates with virulence. However, the precise function of apoptosis in viral infection is not well understood. Reovirus is a neurotropic virus that induces apoptosis in a variety of cell types, including central nervous system neurons, leading to fatal encephalitis in newborn mice. To determine the effect of apoptosis on reovirus replication in the host, we generated two otherwise isogenic viruses that differ in a single amino acid in viral capsid protein 1 that segregates with apoptotic capacity. Apoptosis-proficient and apoptosis-deficient viruses were compared for replication, dissemination, tropism, and tissue injury in newborn mice and for the capacity to spread to uninfected littermates. Our results indicate that apoptotic capacity enhances reovirus replication in the brain and consequent neurovirulence but reduces transmission efficiency. The replication advantage of the apoptosis-proficient strain is limited to the brain and correlates with enhanced infectivity of neurons. These studies reveal a new cell type-specific determinant of reovirus virulence.

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Section: Discussionmentioning

confidence: 75%

Apoptosis Induction Influences Reovirus Replication and Virulence in Newborn Mice

Pruijssers

Hengel

Abel

et al. 2013

J Virol

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“…The S1 gene is a major determinant of reovirus dissemination from the gastrointestinal tract (28,34,44,45). To determine if sequence polymorphisms in the S1 gene contribute to the differences in dissemination of the T3D laboratory isolates from the lungs, we used reverse genetics (35,36) to engineer recombinant T3D F viruses that contain T3D C sequences in the S1 gene (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The polymorphism at nucleotide 77 in the T3D S1 gene affects both of its gene products, 1 and 1s. Interestingly, both S1 gene products are linked to reovirus pathogenesis in vivo (4,5,28,44,48). To determine whether the 1s protein influences viral replication and dissemination from the murine respiratory tract, we used reverse genetics (35,36) to engineer a recombinant rsT3D F /T3D C S1 1s-null virus (Fig.…”

Section: Fig 4 T3dmentioning

confidence: 99%

“…While attachment protein 1 is a major determinant of reovirus pathogenesis (5,30,44,45,67), nonstructural protein 1s also is required for production of maximal viral titers in the gastrointestinal tract (4) and for hematogenous spread after peroral (4) or intramuscular (28) inoculation. Consistent with a role for 1s in viral replication at mucosal sites, our results demonstrate that the T3D C 1s protein enhances viral replication in the respiratory tract and hematogenous dissemination ( Fig.…”

Section: Fig 8 Construction and Characterization Of Rst3dmentioning

confidence: 99%

“…Viruses in which either the T1L (4) or T3D (28) 1s ORF has been ablated produce yields of viral progeny comparable to those of the corresponding wild-type viruses following replication in cell culture. However, 1s-null viruses fail to spread hematogenously in mice following either peroral (4) or intramuscular (28) inoculation. It is not known whether 1s influences viral dissemination following infection in the murine lung.…”

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Genetic Determinants of Reovirus Pathogenesis in a Murine Model of Respiratory Infection

Nygaard

Lahti

Ikizler

et al. 2013

J Virol

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Many viruses invade mucosal surfaces to establish infection in the host. Some viruses are restricted to mucosal surfaces, whereas others disseminate to sites of secondary replication. Studies of strain-specific differences in reovirus mucosal infection and systemic dissemination have enhanced an understanding of viral determinants and molecular mechanisms that regulate viral pathogenesis. After peroral inoculation, reovirus strain type 1 Lang replicates to high titers in the intestine and spreads systemically, whereas strain type 3 Dearing (T3D) does not. These differences segregate with the viral S1 gene segment, which encodes attachment protein 1 and nonstructural protein 1s. In this study, we define genetic determinants that regulate reovirus-induced pathology following intranasal inoculation and respiratory infection. We report that two laboratory isolates of T3D, T3D C and T3D F , differ in the capacity to replicate in the respiratory tract and spread systemically; the T3D C isolate replicates to higher titers in the lungs and disseminates, while T3D F does not. Two nucleotide polymorphisms in the S1 gene influence these differences, and both S1 gene products are involved. T3D C amino acid polymorphisms in the tail and head domains of 1 protein influence the sensitivity of virions to protease-mediated loss of infectivity. The T3D C polymorphism at nucleotide 77, which leads to coding changes in both S1 gene products, promotes systemic dissemination from the respiratory tract. A 1s-null virus produces lower titers in the lung after intranasal inoculation and disseminates less efficiently to sites of secondary replication. These findings provide new insights into mechanisms underlying reovirus replication in the respiratory tract and systemic spread from the lung. Many viruses enter host organisms by invading mucosal surfaces, including those that line the respiratory tract. Infection by some pneumotropic viruses is restricted to the respiratory tract, whereas others replicate in the lung and disseminate to sites of secondary replication. Mammalian orthoreoviruses (reoviruses) naturally infect both the respiratory and gastrointestinal tracts (1). Reovirus strains differ in the capacity to replicate at mucosal sites and disseminate systemically. Studies of strain-specific differences in reovirus mucosal infection and systemic spread have enhanced an understanding of viral determinants and molecular mechanisms that regulate reovirus pathogenesis. For example, after peroral or intratracheal inoculation, reovirus strain type 1 Lang (T1L) replicates to higher titers than does strain type 3 Dearing (T3D) (2). This difference in replication efficiency at the site of primary replication segregates with the reovirus S1 gene segment (2, 3). Like T1L, reassortant virus 3HA1, with nine gene segments from T3D and an S1 gene from T1L, replicates to high titers in mucosal tissues (2). In contrast, reassortant virus 1HA3, with nine gene segments from T1L and an S1 gene from T3D, fails to replicate to high titers at those sit...

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Reovirus Receptors, Cell Entry, and Proapoptotic Signaling

Danthi

Holm

Stehle

et al. 2013

Advances in Experimental Medicine and Biology

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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.

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The Reovirus σ1s Protein Is a Determinant of Hematogenous but Not Neural Virus Dissemination in Mice

Cited by 37 publications

References 46 publications

Apoptosis Induction Influences Reovirus Replication and Virulence in Newborn Mice

Apoptosis Induction Influences Reovirus Replication and Virulence in Newborn Mice

Genetic Determinants of Reovirus Pathogenesis in a Murine Model of Respiratory Infection

Reovirus Receptors, Cell Entry, and Proapoptotic Signaling

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