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Journal of General Virology header logo Journal of General Virology

Volume 92, Issue 4

Tumour necrosis factor alpha (TNF-) stimulation of cells with established dengue virus type 2 infection induces cell death that is accompanied by a reduced ability of TNF- to activate nuclear factor B and reduced sphingosine kinase-1 activity No Access

Abstract

Tumor necrosis factor alpha (TNF-) 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- stimulation cannot activate nuclear factor B (NF-B) to the fullest extent in DENV-2-infected cells. Here, we investigate further responses of DENV-2-infected cells to TNF-, focussing particularly on cell death and pro-survival signals. TNF- stimulation of productively DENV-2-infected monocyte-derived macrophages or HEK-293 cells induced caspase-3-mediated cell death. While TNF- induced comparable degradation of the inhibitor of NF-B alpha (IB-) and NF-B activation in mock-infected and DENV-2-infected cells early in infection, later in infection and coinciding with TNF--induced cell death, TNF--stimulated IB- degradation and NF-B 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--stimulated survival signals. Transfection experiments demonstrated inhibition of TNF--stimulated NF-B activation by expression of DENV-2 capsid (CA) but enhancement by DENV-2 NS5 protein. DENV-2 CA alone, however, did not induce TNF--stimulated cell death or inhibit SphK1 activity. Thus, productively DENV-2-infected cells have compromised TNF--stimulated survival pathways and show enhanced susceptibility to TNF--stimulated cell death, suggesting a role for TNF- in the killing of healthy productively DENV-2-infected cells. Additionally, the altered ability of TNF- to activate NF-B as infection progresses is reflected by the opposing actions of DENV-2 CA and NS5 proteins on TNF--stimulated NF-B activation and could have important consequences for NF-B-driven release of inflammatory cytokines.

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2011-04-01
2025-12-13

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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
J. Gen. Virol. 92, 807 (2011); https://doi.org/10.1099/vir.0.028159-0
/content/journal/jgv/10.1099/vir.0.028159-0
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