Ebola Virus Does Not Block Apoptotic Signaling Pathways

Olejnik, Judith; Alonso, Jesus A.; Schmidt, Kristina Maria; Zhang, Yan; Wang, Wei; Marzi, Andrea; Ebihara, Hideki; Yang, Jinghua; Patterson, Jean L.; Ryabchikova, E. I.; Mühlberger, Elke

doi:10.1128/jvi.01461-12

Cited by 27 publications

(34 citation statements)

References 79 publications

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“…Since high cell density can trigger eIF2␣ phosphorylation (66), we used subconfluent HeLa cells for this experiment. Ars treatment led to eIF2␣ phosphorylation in mock-infected as well as EBOV-infected HeLa cells at all time points examined, indicating that although EBOV is able to block PKR signaling and antagonize eIF2␣ phosphorylation (47,49), it is unable to prevent Ars-induced activation of the signaling pathways leading to SG formation (Fig. 8A).…”

Section: Stress Granules Do Not Form During Ebov Infectionmentioning

confidence: 95%

“…The inhibitory effects of VP35 on PKR, and thus on eIF2␣ phosphorylation, were observed late in infection (1 day p.i. ), when viral protein expression in the infected cells was presumably high (49). Therefore, it is conceivable that PKR might be activated early in infection by incoming EBOV particles or viral transcripts, when the amount of VP35 is still low, and consequently lead to eIF2␣ phosphorylation and SG formation.…”

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confidence: 99%

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Ebola Virus Does Not Induce Stress Granule Formation during Infection and Sequesters Stress Granule Proteins within Viral Inclusions

Nelson

Schmidt

Deflubé

et al. 2016

J Virol

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A hallmark of Ebola virus (EBOV) infection is the formation of viral inclusions in the cytoplasm of infected cells. These viral in-clusions contain the EBOV nucleocapsids and are sites of viral replication and nucleocapsid maturation. Although there is growing evidence that viral inclusions create a protected environment that fosters EBOV replication, little is known about their role in the host response to infection. The cellular stress response is an effective antiviral strategy that leads to stress granule (SG) formation and translational arrest mediated by the phosphorylation of a translation initiation factor, the ␣ subunit of eukaryotic initiation factor 2 (eIF2␣). Here, we show that selected SG proteins are sequestered within EBOV inclusions, where they form distinct granules that colocalize with viral RNA. These inclusion-bound (IB) granules are functionally and structurally different from canonical SGs. Formation of IB granules does not indicate translational arrest in the infected cells. We further show that EBOV does not induce formation of canonical SGs or eIF2␣ phosphorylation at any time postinfection but is unable to fully inhibit SG formation induced by different exogenous stressors, including sodium arsenite, heat, and hippuristanol. Despite the sequestration of SG marker proteins into IB granules, canonical SGs are unable to form within inclusions, which we propose might be mediated by a novel function of VP35, which disrupts SG formation. This function is independent of VP35's RNA binding activity. Further studies aim to reveal the mechanism for SG protein sequestration and precise function within inclusions. IMPORTANCEAlthough progress has been made developing antiviral therapeutics and vaccines against the highly pathogenic Ebola virus (EBOV), the cellular mechanisms involved in EBOV infection are still largely unknown. To better understand these intracellular events, we investigated the cellular stress response, an antiviral pathway manipulated by many viruses. We show that EBOV does not induce formation of stress granules (SGs) in infected cells and is therefore unrestricted by their concomitant translational arrest. We identified SG proteins sequestered within viral inclusions, which did not impair protein translation. We further show that EBOV is unable to block SG formation triggered by exogenous stress early in infection. These findings provide insight into potential targets of therapeutic intervention. Additionally, we identified a novel function of the interferon antagonist VP35, which is able to disrupt SG formation.

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Section: Stress Granules Do Not Form During Ebov Infectionmentioning

confidence: 95%

mentioning

confidence: 99%

Ebola Virus Does Not Induce Stress Granule Formation during Infection and Sequesters Stress Granule Proteins within Viral Inclusions

Nelson

Schmidt

Deflubé

et al. 2016

J Virol

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“…Interestingly, selective apoptosis induced by a dsRNA-dependent caspase recruiter strongly inhibited virus replication, suggesting that apoptosis might be capable of playing an important role in overcoming filovirus infection [25]. Thus, modulation of the signaling machinery including the Fas/FasL interaction may therefore be a useful strategy for the development of antiviral therapeutics.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

“…Although upregulation of TRAIL and Fas molecules associated with EBOV infection of humans and experimentally infected animals has been reported [21,22,23,24,25], it was shown that EBOV did not naturally induce apoptosis in infected cells in vitro. However, no suppressive effect on the TRAIL-induced apoptotic signal has been observed in EBOV-infected cells [25]. In this study, we focused on Fas-mediated signaling, which is one of the major extrinsic pathways for the induction of apoptosis, and found that filovirus GPs formed a steric shield on the cell surface and that GP-expressing cells showed resistance to Fas-induced cell death, suggesting that interference with apoptotic signal transduction may serve as an immune evasion mechanism of filoviruses.…”

Section: Introductionmentioning

confidence: 97%

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Suppression of Fas-mediated apoptosis via steric shielding by filovirus glycoproteins

Noyori

Nakayama

Maruyama

et al. 2013

Biochemical and Biophysical Research Communications

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Filovirus Strategies to Escape Antiviral Responses

Olejnik

Hume

Leung

et al. 2017

Current Topics in Microbiology and Immunology

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This chapter describes the various strategies filoviruses use to escape host immune responses with a focus on innate immune and cell death pathways. Since filovirus replication can be efficiently blocked by interferon (IFN), filoviruses have evolved mechanisms to counteract both type I IFN induction and IFN response signaling pathways. Intriguingly, marburg- and ebolaviruses use different strategies to inhibit IFN signaling. This chapter also summarizes what is known about the role of IFN-stimulated genes (ISGs) in filovirus infection. These fall into three categories: those that restrict filovirus replication, those whose activation is inhibited by filoviruses, and those that have no measurable effect on viral replication. In addition to innate immunity, mammalian cells have evolved strategies to counter viral infections, including the induction of cell death and stress response pathways, and we summarize our current knowledge of how filoviruses interact with these pathways. Finally, this chapter delves into the interaction of EBOV with myeloid dendritic cells and macrophages and the associated inflammatory response, which differs dramatically between these cell types when they are infected with EBOV. In summary, we highlight the multifaceted nature of the host-viral interactions during filoviral infections.

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Ebola Virus Does Not Block Apoptotic Signaling Pathways

Cited by 27 publications

References 79 publications

Ebola Virus Does Not Induce Stress Granule Formation during Infection and Sequesters Stress Granule Proteins within Viral Inclusions

Ebola Virus Does Not Induce Stress Granule Formation during Infection and Sequesters Stress Granule Proteins within Viral Inclusions

Suppression of Fas-mediated apoptosis via steric shielding by filovirus glycoproteins

Filovirus Strategies to Escape Antiviral Responses

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