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https://hdl.handle.net/2440/66497
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Type: | Journal article |
Title: | Tumour necrosis factor alpha (TNF-α) stimulation of cells with established dengue virus type 2 infection induces cell death that is accompanied by a reduced ability of TNF-α to activate nuclear factor κB and reduced sphingosine kinase-1 activity |
Other Titles: | Tumour necrosis factor alpha (TNF-alpha) stimulation of cells with established dengue virus type 2 infection induces cell death that is accompanied by a reduced ability of TNF-alpha to activate nuclear factor kappaB and reduced sphingosine kinase-1 activity |
Author: | Wati, S. Rawlinson, S. Ivanov, R. Dorstyn, L. Beard, M. Jans, D. Pitson, S. Burrell, C. Li, P. Carr, J. |
Citation: | Journal of General Virology, 2011; 92(4):807-818 |
Publisher: | Soc General Microbiology |
Issue Date: | 2011 |
ISSN: | 0022-1317 1465-2099 |
Statement of Responsibility: | Satiya Wati, Stephen M. Rawlinson, Ruby A. Ivanov, Loretta Dorstyn, Michael R. Beard, David A. Jans, Stuart M. Pitson, Christopher J. Burrell, Peng Li and Jillian M. Carr |
Abstract: | Tumor necrosis factor alpha (TNF-α) has an antiviral role in some infections but in dengue virus (DENV) infection it is linked to severe pathology. We have previously shown that TNF-α stimulation cannot activate nuclear factor κB (NF-κB) to the fullest extent in DENV-2-infected cells. Here, we investigate further responses of DENV-2-infected cells to TNF-α, focussing particularly on cell death and pro-survival signals. TNF-α stimulation of productively DENV-2-infected monocyte-derived macrophages or HEK-293 cells induced caspase-3-mediated cell death. While TNF-α induced comparable degradation of the inhibitor of NF-κB alpha (IκB-α) and NF-κB activation in mock-infected and DENV-2-infected cells early in infection, later in infection and coinciding with TNF-α-induced cell death, TNF-α-stimulated IκB-α degradation and NF-κB activation was reduced. This was associated with reduced levels of sphingosine kinase-1 (SphK1) activity in DENV-2-infected cells; SphK1 being a known mediator of TNF-α-stimulated survival signals. Transfection experiments demonstrated inhibition of TNF-α-stimulated NF-κB activation by expression of DENV-2 capsid (CA) but enhancement by DENV-2 NS5 protein. DENV-2 CA alone, however, did not induce TNF-α-stimulated cell death or inhibit SphK1 activity. Thus, productively DENV-2-infected cells have compromised TNF-α-stimulated survival pathways and show enhanced susceptibility to TNF-α-stimulated cell death, suggesting a role for TNF-α in the killing of healthy productively DENV-2-infected cells. Additionally, the altered ability of TNF-α to activate NF-κB as infection progresses is reflected by the opposing actions of DENV-2 CA and NS5 proteins on TNF-α-stimulated NF-κB activation and could have important consequences for NF-κB-driven release of inflammatory cytokines. |
Keywords: | Cells, Cultured Macrophages Epithelial Cells Humans Dengue Virus Phosphotransferases (Alcohol Group Acceptor) Tumor Necrosis Factor-alpha NF-kappa B Cell Death |
Rights: | © 2011 SA Pathology |
DOI: | 10.1099/vir.0.028159-0 |
Published version: | http://dx.doi.org/10.1099/vir.0.028159-0 |
Appears in Collections: | Aurora harvest Molecular and Biomedical Science publications |
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