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

The ability of dendritic cells (DCs) to shape the adaptive immune response to viral infection is mediated largely by their maturation and activation s tate as determined by the surface expression of HLA molecules, costimulator y molecules, and cytokine production. Dengue is an emerging arboviral disea se where the severity of illness is influenced by the adaptive immune respo nse to the virus. In this report, we have demonstrated that dengue virus in fects and replicates in immature human myeloid DCs. Exposure to live dengue virus led to maturation and activation of both the infected and surroundin g, uninfected DCs and stimulated production of tumor necrosis factor alpha (TNF-alpha) and alpha interferon (IFN-alpha). Activation of the dengue viru s-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 v irus 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 vi rus in natural infection and the vigor of CMI is modulated by the relative presence or absence of IFN-gamma in the microenvironment surrounding the vi rus-infected DCs. These findings are relevant to understanding the pathogen esis of dengue hemorrhagic fever and the design of new vaccination and ther apeutic strategies.