IFN-c Production Depends on IL-12 and IL-18 Combined Action and Mediates Host Resistance to Dengue Virus Infection in a Nitric Oxide-Dependent Manner

Dengue is a mosquito-borne disease caused by one of four serotypes of Dengue virus (DENV-1–4). Severe dengue infection in humans is characterized by thrombocytopenia, increased vascular permeability, hemorrhage and shock. However, there is little information about host response to DENV infection. Here, mechanisms accounting for IFN-c production and effector function during dengue disease were investigated in a murine model of DENV-2 infection. IFN-c expression was greatly increased after infection of mice and its production was preceded by increase in IL-12 and IL-18 levels. In IFN-c2/2 mice, DENV-2-associated lethality, viral loads, thrombocytopenia, hemoconcentration, and liver injury were enhanced, when compared with wild type-infected mice. IL-12p402/2 and IL-182/2 infected-mice showed decreased IFN-c production, which was accompanied by increased disease severity, higher viral loads and enhanced lethality. Blockade of IL-18 i