Reovirus nonstructural protein σ1s is required for establishment of viremia and systemic dissemination

Boehme, Karl W.; Guglielmi, Kristen M.; Dermody, Terence S.

doi:10.1073/pnas.0907412106

Cited by 59 publications

(97 citation statements)

References 46 publications

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“…At both 24 and 48 h postinfection, no differences in protein levels were observed between the wild-type and mutant viruses. Together, these data are consistent with previous studies showing that 1s is dispensable for reovirus replication in cultured cells (6,32).…”

Section: Resultssupporting

confidence: 83%

“…Receptor engagement is critical for target cell selection by many viruses, suggesting that the 1 attachment protein is the primary determinant of viral tropism. However, 1s is required for hematogenous dissemination of type 1 reovirus to sites of secondary replication in mice (6). Because of the serotype-specific differences in reovirus tropism, routes of spread, and outcome of infection, it is possible that the 1s protein from different serotypes mediates serotype-specific functions.…”

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confidence: 99%

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

Boehme

Frierson

Konopka

et al. 2011

J Virol

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Nonstructural protein 1s is a critical determinant of hematogenous dissemination by type 1 reoviruses, which reach the central nervous system (CNS) by a strictly blood-borne route. However, it is not known whether 1s contributes to neuropathogenesis of type 3 reoviruses, which disseminate by both vascular and neural pathways. Using isogenic type 3 viruses that vary only in 1s expression, we observed that mice survived at a higher frequency following hind-limb inoculation with 1s-null virus than when inoculated with wild-type virus. This finding suggests that 1s is essential for reovirus virulence when inoculated at a site that requires systemic spread to cause disease. Wild-type and 1s-null viruses produced comparable titers in the spinal cord, suggesting that 1s is dispensable for invasion of the CNS. Although the two viruses ultimately achieved similar peak titers in the brain, loads of wild-type virus were substantially greater than those of the 1s-null mutant at early times after inoculation. In contrast, wild-type virus produced substantially higher titers than the 1s-null virus in peripheral organs to which reovirus spreads via the blood, including the heart, intestine, liver, and spleen. Concordantly, viral titers in the blood were higher following infection with wild-type virus than following infection with the 1s-null mutant. These results suggest that differences in viral brain titers at early time points postinfection are due to limited virus delivery to the brain by hematogenous pathways. Transection of the sciatic nerve prior to hind-limb inoculation diminished viral spread to the spinal cord. However, wild-type virus retained the capacity to disseminate to the brain following sciatic nerve transection, indicating that wild-type reovirus can spread to the brain by the blood. Together, these results indicate that 1s is not required for reovirus spread by neural mechanisms. Instead, 1s mediates hematogenous dissemination within the infected host, which is required for full reovirus neurovirulence.

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Section: Resultssupporting

confidence: 83%

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confidence: 99%

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

Boehme

Frierson

Konopka

et al. 2011

J Virol

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“…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%

“…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 sites, like T3D (2). The S1 gene also is associated with the capacity of reovirus to spread systemically from the enteric tract (4,5). After gastrointestinal infection, 3HA1, like T1L, spreads to sites of secondary replication, whereas 1HA3, like T3D, does not (5).…”

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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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“…A plasmid-based reverse genetics system was more recently described for mammalian reovirus by the group of Dr Terence Dermody (Kobayashi et al, 2007;reviewed by: Lemay, 2011); this novel approach was used by this group to study various reovirus mutants obtained by site-directed mutagenesis (see for example: (Boehme, Guglielmi, and Dermody, 2009;Danthi et al, 2008a;Danthi et al, 2008b;Kobayashi et al, 2007;Kobayashi et al, 2009)), or to substitute a whole gene segment from one reovirus serotype to the other (Kobayashi et al, 2007;Zurney et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

Addition of exogenous polypeptides on the mammalian reovirus outer capsid using reverse genetics

Brochu-Lafontaine

Lemay

2012

Journal of Virological Methods

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Addition of exogenous peptide sequences on viral capsids is a powerful approach to study the process of viral infection or to retarget viruses toward defined cell types. Until recently, it was not possible to manipulate the genome of mammalian reovirus and this was an obstacle to the addition of exogenous sequence tags onto the capsid of a replicating virus. This obstacle has now been overcome by the advent of the plasmid-based reverse genetics system. In the present study, reverse genetics was used to introduce different exogenous peptides, up to 40 amino acids long, at the carboxyl-terminal end of the σ1 outer capsid protein. The tagged viruses obtained were infectious, produce plaques of similar size, and could be easily propagated at hight titers. However, attempts to introduce a 750 nucleotides-long sequence failed, even when it was added after the stop codon, suggesting a possible size limitation at the nucleic acid level.

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Reovirus nonstructural protein σ1s is required for establishment of viremia and systemic dissemination

Cited by 59 publications

References 46 publications

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

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

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

Addition of exogenous polypeptides on the mammalian reovirus outer capsid using reverse genetics

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