Phosphoinositide-3 Kinase-Akt Pathway Controls Cellular Entry of Ebola Virus

Saeed, Mohammad; Kolokoltsov, Andrey A.; Freiberg, Alexander N.; Holbrook, Michael R.; Davey, Robert A.

doi:10.1371/journal.ppat.1000141

Cited by 177 publications

(200 citation statements)

References 54 publications

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“…It is only its endosomal release into the cytoplasm that requires an endosomolytic agent such as perforin (29,32). Various viruses are known to carry molecules with such properties to enable their endocytic entry into the cytoplasm after cellular uptake (29,(33)(34)(35). Consequently, a series of studies have shown that virus particles can enable a cytotoxic effect of GrB in the absence of perforin (29,36).…”

Section: Discussionmentioning

confidence: 99%

Human B Cells Secrete Granzyme B When Recognizing Viral Antigens in the Context of the Acute Phase Cytokine IL-21

Hagn

Schwesinger²,

Ebel³

et al. 2009

The Journal of Immunology

111

116

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Human B cells are currently not known to produce the proapoptotic protease granzyme B (GrB) in physiological settings. We have discovered that BCR stimulation with either viral Ags or activating Abs in the context of the acute phase cytokine IL-21 can induce the secretion of substantial amounts of GrB by human B cells. Importantly, GrB response to viral Ags was significantly stronger in B cells from subjects recently vaccinated against the corresponding viruses as compared with unvaccinated subjects. GrB-secreting B cells featured a homogeneous CD19+CD20+CD27−CD38−IgD− phenotype, improved survival, and enhanced expression of costimulatory, Ag-presenting and cell-adhesion molecules. B cell-derived GrB was enzymatically active and its induction required the activation of similar signaling pathways as those in CTLs. Our findings suggest that GrB-secreting B cells support the early antiviral immune response against viruses with endosomal entry pathways, thereby counteracting overwhelming viral replication at the beginning of an infection until virus-specific T cells from draining lymph nodes arrive at the site of infection. Our data may also explain the elevated serum GrB levels found in the early phase of various viral diseases.

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Section: Discussionmentioning

confidence: 99%

Human B Cells Secrete Granzyme B When Recognizing Viral Antigens in the Context of the Acute Phase Cytokine IL-21

Hagn

Schwesinger²,

Ebel³

et al. 2009

The Journal of Immunology

111

116

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“…As viruses can manipulate or make use of the cytoskeletal network of actin filaments during their life cycles, (virus-induced) Rac1 activity has been linked to viral infection or protein trafficking processes as well as the spread of several viruses causing severe human diseases, for example, HIV (Lu et al, 1996), Ebola (Saeed et al, 2008), HSV-1 (Hoppe et al, 2006), HBV (Gros et al, 2008) and paramyxoviruses, for example, Hendra virus (Schowalter et al, 2006). From rodent experiments Rac1 is known to have oncogenic activity and to be involved in tumorigenesis (Kissil et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Rac1 is required for oncolytic NDV replication in human cancer cells and establishes a link between tumorigenesis and sensitivity to oncolytic virus

et al. 2010

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Oncolytic Newcastle disease virus (NDV) replicates selectively in most human tumor cells but not in normal cells. The relationship between tumorigenesis and the selective susceptibility of most tumor cells to oncolytic NDV replication is poorly understood. A multistage skin carcinogenesis model derived from non-tumorigenic HaCaT cells was used to systematically investigate the molecular mechanisms involved in the oncolytic NDVsensitivity associated with tumorigenic transformation. No significant differences in interferon signaling were observed between the virus-sensitive tumor cells and the virus-resistant non-tumorigenic parental cells. Oncogenic H-Ras, which had been used for tumorigenic transformation, was shown to be necessary for virus replication but was not sufficient to render cells susceptible to NDV replication. By using an siRNA screening approach to search for virus-sensitizing genes in the tumorigenic cells, we could identify the small GTPase Rac1 as an oncogenic protein that is essential for NDV replication and anchorage-independent growth in tumorigenic cells. Furthermore, Rac1 expression was sufficient to render non-tumorigenic cells susceptible to NDV replication and to oncolytic cytotoxicity. This study establishes Rac1 as a link between tumorigenesis and oncolytic virus sensitivity in the HaCaT multistage skin carcinogenesis model.

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“…Many viruses exploit the PI3K/Akt pathway to facilitate various steps in their replication cycle, such as regulation of gene expression and genome replication. However, our study does not rule out the possibility that inhibition of PI3K/Akt activation blocks entry of PCV2 into host cells, as described for Ebola virus (45), thereby reducing viral DNA replication and viral protein synthesis and causing lower production of infectious virus particles in the PCV2-infected cells. (20 M).…”

Section: Discussionmentioning

confidence: 69%

“…1C); virus receptor attachment and/or cell entry might be required for PI3K/Akt activation in the PCV2-infected cells, as described for some other viruses (28,29,40,64). During their entry into cells, adenovirus, adenovirus-associated virus, respiratory syncytial virus, and Ebola virus all have the ability to promote PI3K/Akt signaling without expression of viral products (28,29,35,40,45,64). Also, the PI3K/Akt pathway is simultaneously induced by intracellular viral proteins and particle adhesion during the internalization process of some viruses, including human papillomavirus (17), influenza A virus (14), respiratory syncytial virus (30), and bovine herpesvirus type 1 (66).…”

Section: Discussionmentioning

confidence: 92%

“…It has been shown that mTORC1 controls cell growth and cap-dependent translation and mTORC2 regulates the actin cytoskeleton. For virus infections, the PI3K/Akt pathway plays an important role in virus life cycle, from virus entry through viral transcription and protein synthesis, and in enhanced cell survival by blockage of apoptosis in infected cells, oncogenic transformation, and virion assembly (5,12,16,18,19,23,25,37,43,45,50,66).…”

mentioning

confidence: 99%

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Activation of the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway during Porcine Circovirus Type 2 Infection Facilitates Cell Survival and Viral Replication

Zhu

Wang

et al. 2012

J Virol

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Virus infection activates host cellular signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which regulates diverse cellular activities related to cell growth, survival, and apoptosis. The present study demonstrated for the first time that porcine circovirus type 2 (PCV2), a major causative agent of postweaning multisystemic wasting syndrome, which is an emerging and important swine disease, can transiently induce the PI3K/Akt pathway in cultured cells at an early step during PCV2 infection. Activation of the PI3K/Akt signal was also induced by UV-irradiated PCV2, indicating that virus replication was not required for this induction. Inhibition of PI3K activation leads to reduced virus yield, which is associated with decreased viral DNA replication and lower virus protein expression. However, inhibition of PI3K activation greatly enhanced apoptotic responses as evidenced by the cleavage of poly-ADP ribose polymerase and caspase-3 as well as DNA fragmentation using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling staining during the early stage of PCV2 infection. Furthermore, the pancaspase inhibitor zVAD.fmk alleviated the reduction in Akt phosphorylation levels by inhibiting PI3K activation, indicating that the signaling promotes cell survival and thereby favors viral replication. These results reveal that an antiapoptotic role for the PI3K/Akt pathway induced by PCV2 infection to suppress premature apoptosis for improved virus growth after infection, extending our understanding of the molecular mechanism of PCV2 infection.

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Phosphoinositide-3 Kinase-Akt Pathway Controls Cellular Entry of Ebola Virus

Cited by 177 publications

References 54 publications

Human B Cells Secrete Granzyme B When Recognizing Viral Antigens in the Context of the Acute Phase Cytokine IL-21

Human B Cells Secrete Granzyme B When Recognizing Viral Antigens in the Context of the Acute Phase Cytokine IL-21

Rac1 is required for oncolytic NDV replication in human cancer cells and establishes a link between tumorigenesis and sensitivity to oncolytic virus

Activation of the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway during Porcine Circovirus Type 2 Infection Facilitates Cell Survival and Viral Replication

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