Reovirus Infection or Ectopic Expression of Outer Capsid Protein μ1 Induces Apoptosis Independently of the Cellular Proapoptotic Proteins Bax and Bak

Wisniewski, Meagan L.; Werner, Brenda G.; Hom, Louis G.; Anguish, Lynne J.; Coffey, Caroline M.; Parker, John S. L.

doi:10.1128/jvi.01982-10

Cited by 27 publications

(31 citation statements)

References 34 publications

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“…To determine whether T1 and T3 reovirus strains differ in the capacity to replicate in the murine respiratory tract, we inoculated CBA/J mice intranasally with 10 7 PFU of T1L, T3D C , or T3D F and quantified viral titers in the lungs at days 1, 3, and 5 postinoculation. Since the T3D C and T3D F isolates of prototype reovirus strain T3D display a variety of distinct in vitro phenotypes (41)(42)(43), both isolates were used in our study. We found that inoculation with T1L produced significantly higher titers in the lungs than did T3D F (Fig.…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

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

Nygaard

Lahti

Ikizler

et al. 2013

J Virol

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“…Importantly, Bax is essential for apoptosis induced by dsRNA (12), but the role of Bax in reovirus-induced apoptosis is not completely understood. In cultured cells, reovirus apoptosis occurs independently of Bax and Bak, as levels of apoptosis in MEFs lacking Bax and Bak are equivalent to those in wild-type cells (89). However, in Bax-deficient mice, reovirus produces less apoptosis and tissue damage in the CNS than those observed for wild-type mice (9).…”

Section: Fig 5 Reovirus Replication Is Not Influenced By Noxa Expressmentioning

confidence: 95%

Apoptosis Induced by Mammalian Reovirus Is Beta Interferon (IFN) Independent and Enhanced by IFN Regulatory Factor 3- and NF-κB-Dependent Expression of Noxa

Knowlton

Dermody

Holm

2012

J Virol

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“…Recently it was reported that reovirus protein 1, an outer capsid viral protein crucial for pathogenesis, is able to release both cyt c and Smac when overexpressed in fibroblasts, and T3D infection of Bax Ϫ/Ϫ Bak Ϫ/Ϫ mouse embryonic fibroblasts (MEFs) also results in the release of cyt c (81). To determine if cyt c is released in reovirus-infected neurons in vivo in the absence of Bax, immunofluorescence staining was also performed for cyt c in mockand T3D-infected Bax Ϫ/Ϫ mice at 9 dpi (Fig.…”

Section: Vol 85 2011 Bax Is Important For Reovirus Pathogenesis In mentioning

confidence: 99%

The Proapoptotic Bcl-2 Protein Bax Plays an Important Role in the Pathogenesis of Reovirus Encephalitis

Berens

Tyler

2011

J Virol

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Encephalitis induced by reovirus serotype 3 (T3) strains results from the apoptotic death of infected neurons. Extrinsic apoptotic signaling is activated in reovirus-infected neurons in vitro and in vivo, but the role of intrinsic apoptosis signaling during encephalitis is largely unknown. Bax plays a key role in intrinsic apoptotic signaling in neurons by allowing the release of mitochondrial cytochrome c. We found Bax activation and cytochrome c release in neurons following infection of neonatal mice with T3 reoviruses. Bax ؊/؊ mice infected with T3 Abney (T3A) have reduced central nervous system (CNS) tissue injury and decreased apoptosis, despite viral replication that is similar to that in wild-type (WT) Bax ؉/؉ mice. In contrast, in the heart, T3A-infected Bax ؊/؊ mice have viral growth, caspase activation, and injury comparable to those in WT mice, indicating that the role of Bax in pathogenesis is organ specific. Nonmyocarditic T3 Dearing (T3D)-infected Bax ؊/؊ mice had delayed disease and enhanced survival compared to WT mice. T3D-infected Bax ؊/؊ mice had significantly lower viral titers and levels of activated caspase 3 in the brain despite unaffected transneuronal spread of virus. Cytochrome c and Smac release occurred in some reovirus-infected neurons in the absence of Bax; however, this was clearly reduced compared to levels seen in Bax ؉/؉ wild-type mice, indicating that Bax is necessary for efficient activation of proapoptotic mitochondrial signaling in infected neurons. Our studies suggest that Bax is important for reovirus growth and pathogenesis in neurons and that the intrinsic pathway of apoptosis, mediated by Bax, is important for full expression of disease, CNS tissue injury, apoptosis, and viral growth in the CNS of reovirus-infected mice.

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Reovirus Infection or Ectopic Expression of Outer Capsid Protein μ1 Induces Apoptosis Independently of the Cellular Proapoptotic Proteins Bax and Bak

Cited by 27 publications

References 34 publications

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

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

Apoptosis Induced by Mammalian Reovirus Is Beta Interferon (IFN) Independent and Enhanced by IFN Regulatory Factor 3- and NF-κB-Dependent Expression of Noxa

The Proapoptotic Bcl-2 Protein Bax Plays an Important Role in the Pathogenesis of Reovirus Encephalitis

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