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. 2001 Apr;75(8):3501-8.
doi: 10.1128/JVI.75.8.3501-3508.2001.

Human dendritic cells are activated by dengue virus infection: enhancement by gamma interferon and implications for disease pathogenesis

D H Libraty  1 , S Pichyangkul, C Ajariyakhajorn, T P Endy, F A Ennis
Affiliations

Human dendritic cells are activated by dengue virus infection: enhancement by gamma interferon and implications for disease pathogenesis

D H Libraty et al. J Virol. 2001 Apr.

Abstract

The ability of dendritic cells (DCs) to shape the adaptive immune response to viral infection is mediated largely by their maturation and activation state as determined by the surface expression of HLA molecules, costimulatory molecules, and cytokine production. Dengue is an emerging arboviral disease where the severity of illness is influenced by the adaptive immune response to the virus. In this report, we have demonstrated that dengue virus infects and replicates in immature human myeloid DCs. Exposure to live dengue virus led to maturation and activation of both the infected and surrounding, uninfected DCs and stimulated production of tumor necrosis factor alpha (TNF-alpha) and alpha interferon (IFN-alpha). Activation of the dengue virus-infected DCs was blunted compared to the surrounding, uninfected DCs, and dengue virus infection induced low-level release of interleukin-12 p70 (IL-12 p70), a key cytokine in the development of cell-mediated immunity (CMI). Upon the addition of IFN-gamma, there was enhanced activation of dengue virus-infected DCs and enhanced dengue virus-induced IL-12 p70 release. The data suggest a model whereby DCs are the early, primary target of dengue virus in natural infection and the vigor of CMI is modulated by the relative presence or absence of IFN-gamma in the microenvironment surrounding the virus-infected DCs. These findings are relevant to understanding the pathogenesis of dengue hemorrhagic fever and the design of new vaccination and therapeutic strategies.

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Figures

FIG. 1
FIG. 1
Dengue virus productively infects immature myeloid DCs, and infection is decreased in the presence of IFN-γ. Immature myeloid DCs were infected with DEN-2 16681 (MOI = 5) in the absence or presence of rIFN-γ (100 U/ml). At 48 h, cells were stained for surface CD1a and intracellular DEN-2, and cell culture supernatants were collected. (A) Percent DEN-2-infected CD1a+ DCs determined by cytofluorometry; (B) virus titer in cell culture supernatants. The results of six independent experiments are shown. Each symbol represents one individual.
FIG. 2
FIG. 2
Dengue virus infection induces DC maturation and activation. Immature myeloid DCs were infected with DEN-2 16681 (MOI = 5) or mock infected. At 48 h following virus adsorption, three-color cytofluorometry of the DCs was performed. The following markers were evaluated: (i) presence of intracellular DEN-2 virus; (ii) surface expression of CD83, CD40, CD80, CD86, HLA class I, or HLA class II; and (iii) surface expression of CD1a. All analyses were performed on the CD1a+ cell population gate. (A) FACS profiles of mock-infected (control) CD1a+ DCs; (B) FACS profiles of dengue virus-infected CD1a+ DCs after virus adsorption (DEN-2+ gate, far right histogram); (C) FACS profiles of uninfected (bystander) DCs after virus adsorption (DEN-2− gate, far right histogram). Open peaks, isotype control; shaded peaks, specific antibody staining. One representative experiment of six is shown.
FIG. 3
FIG. 3
Dengue virus infection induces TNF-α and IFN-γ release from myeloid DCs. Immature myeloid DCs were infected with DEN-2 16681 (MOI = 5) or mock infected. Cell-free supernatants were collected at 48 h and assayed for TNF-α (A) and IFN-γ (B) release by ELISA. The results of six independent experiments are shown. Values are the means of duplicate determinations. Each symbol represents one individual.
FIG. 4
FIG. 4
IFN-γ enhances dengue virus-induced IL-12 p70 release from myeloid DCs. Immature myeloid DCs were infected with DEN-2 16681 (MOI = 5) or mock infected in the presence or absence of IFN-γ (100 U/ml). Cell-free supernatants were collected at 48 h and assayed for IL-12 p70 release by ELISA. (A) IL-12 p70 production in the absence of exogenous IFN-γ (n = 6); (B) IL-12 p70 production in the presence of exogenous IFN-γ (100 U/ml) (n = 4). Values are the means of duplicate determinations. Each symbol represents one individual.
FIG. 5
FIG. 5
Dengue virus infection does not induce IL-10 release from myeloid DCs. Immature myeloid DCs were infected with DEN-2 16681 (MOI = 5) or mock infected in the presence or absence of IFN-γ (100 U/ml). Cell-free supernatants were collected at 48 h and assayed for IL-10 release by ELISA. The results of six independent experiments are shown. Values are the means of duplicate determinations. Each symbol represents one individual.
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