Intracellular Events and Cell Fate in Filovirus Infection

Olejnik, Judith; Ryabchikova, E. I.; Corley, Ronald B.; Mühlberger, Elke

doi:10.3390/v3081501

Cited by 81 publications

(111 citation statements)

References 213 publications

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“…In patients, EBOV hemorrhagic fever is associated with a "cytokine storm" late in infection, and the dysregulated cytokine response appears to be associated with fatal outcomes (4,12). Interestingly, only minimal cellular inflammatory responses occur at the sites of infection (2). With the recent discovery of necrotic signaling pathways, future studies could help determine if necrosis plays a role in EBOV pathogenesis, a process that is still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…Due to the high lethality rate and the lack of licensed vaccines and treatments, EBOV is classified as a biosafety level 4 (BSL4) pathogen and a NIAID category A priority pathogen (1). EBOV productively infects a variety of cells and tissues, with monocytes, macrophages, and dendritic cells representing the early target cells of infection (2). Lymphocytes remain uninfected by EBOV, but a decrease in lymphocyte numbers due to bystander apoptosis is observed during EBOV infection (3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

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Ebola Virus Does Not Block Apoptotic Signaling Pathways

Olejnik

Alonso

Schmidt

et al. 2013

J Virol

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Ebola Virus Does Not Block Apoptotic Signaling Pathways

Olejnik

Alonso

Schmidt

et al. 2013

J Virol

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“…Postmortem studies of patients and experimentally infected animals have demonstrated that infection of immune cells (macrophages, monocytes, and dendritic cells), epithelial and endothelial cells, fibroblasts, hepatocytes, and adrenal gland tissue (22,23). It is believed that Ebola viruses exhibit a preference for mononuclear cells in the early stage of infection for rapid virus replication (24,25).…”

Section: Ebola Virus Diseasementioning

confidence: 99%

Addressing Therapeutic Options for Ebola Virus Infection in Current and Future Outbreaks

Haque

Hober

Blondiaux³

2015

Antimicrob Agents Chemother

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c Ebola virus can cause severe hemorrhagic disease with high fatality rates. Currently, no specific therapeutic agent or vaccine has been approved for treatment and prevention of Ebola virus infection of humans. Although the number of Ebola cases has fallen in the last few weeks, multiple outbreaks of Ebola virus infection and the likelihood of future exposure highlight the need for development and rapid evaluation of pre-and postexposure treatments. Here, we briefly review the existing and future options for anti-Ebola therapy, based on the data coming from rare clinical reports, studies on animals, and results from in vitro models. We also project the mechanistic hypotheses of several potential drugs against Ebola virus, including small-molecule-based drugs, which are under development and being tested in animal models or in vitro using various cell types. Our paper discusses strategies toward identifying and testing anti-Ebola virus properties of known and medically approved drugs, especially those that can limit the pathological inflammatory response in Ebola patients and thereby provide protection from mortality. We underline the importance of developing combinational therapy for better treatment outcomes for Ebola patients.

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“…), as observed by electron microscopy (14). Eventually, tubular structures appear in this granular material, representing the newly synthesized nucleocap-sids that assemble into small inclusions (10,(14)(15)(16). At later stages of infection, the inclusions fuse together to become larger and more irregularly shaped, but they remain dynamic structures (10).…”

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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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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Intracellular Events and Cell Fate in Filovirus Infection

Cited by 81 publications

References 213 publications

Ebola Virus Does Not Block Apoptotic Signaling Pathways

Ebola Virus Does Not Block Apoptotic Signaling Pathways

Addressing Therapeutic Options for Ebola Virus Infection in Current and Future Outbreaks

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

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