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

Abstract

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-γ production and effector function during dengue disease were investigated in a murine model of DENV-2 infection. IFN-γ expression was greatly increased after infection of mice and its production was preceded by increase in IL-12 and IL-18 levels. In IFN-γ−/− mice, DENV-2-associated lethality, viral loads, thrombocytopenia, hemoconcentration, and liver injury were enhanced, when compared with wild type-infected mice. IL-12p40−/− and IL-18−/− infected-mice showed decreased IFN-γ production, which was accompanied by increased disease severity, higher viral loads and enhanced lethality. Blockade of IL-18 in infected IL-12p40−/− mice resulted in complete inhibition of IFN-γ production, greater DENV-2 replication, and enhanced disease manifestation, resembling the response seen in DENV-2-infected IFN-γ−/− mice. Reduced IFN-γ production was associated with diminished Nitric Oxide-synthase 2 (NOS2) expression and NOS2−/− mice had elevated lethality, more severe disease evolution and increased viral load after DENV-2 infection. Therefore, IL-12/IL-18-induced IFN-γ production and consequent NOS2 induction are of major importance to host resistance against DENV infection.

Normal Free Interleukin-18 (IL-18) Plasma Levels in Dengue Virus Infection and the Need To Measure Both Total IL-18 and IL-18 Binding Protein Levels

“…However, the interpretation of these data is limited by the fact that no information on its natural antagonist IL-18BP is given as well. The same applies to the in vitro and animal studies that also suggested an important role for IL-18 in the pathogenesis of dengue virus (7)(8)(9). In the present study, we document high plasma IL-18 levels concurring with increased IL- tumor necrosis factor alpha (TNF-␣) (C), IL-6 (D), and IL-1 receptor antagonist (IL-1Ra) (E) in Indonesian adults with dengue fever (n ϭ 95) during the febrile (n ϭ 14), critical (n ϭ 77), early recovery (n ϭ 72), and convalescence (n ϭ 54) phases; with leptospirosis (n ϭ 19); and with enteric fever (n ϭ 6) and in a control group of healthy adult Indonesians (n ϭ 22).…”

“…IL-18, together with IL-12, plays a major role in the production of gamma interferon (IFN-␥). This was also shown in a murine dengue model, in which IL-18 acted in synergism with IL-12 to induce IFN-␥ and other T-helper 1 cytokines, which are considered central mediators in dengue host defense (8,9).…”

“…IFN-␥ production can be induced, as shown in a murine dengue model, by the combined action of IL-18 and IL-12, while blocking IL-18 activity by administration of recombinant IL-18BP results in lower IFN-␥ levels, higher TNF-␣ and IL-6 serum levels, and more severe disease (8). In contrast, the present study showed that IFN-␥ was increased during the febrile phase of dengue, while IL-18 levels were unchanged.…”

Type I IFNs and IL-18 Regulate the Antiviral Response of Primary Human γδ T Cells against Dendritic Cells Infected with Dengue Virus

“…Because an increased capacity to mount cytotoxic responses toward DVinfected target cells was associated with a decreased likelihood of developing severe dengue disease (7), the ability of IL-18 to enhance the cytotoxic responses of gd T cells against DV-infected targets might be an important determinant of dengue disease severity. Further studies will be required to address this possibility, particularly because it is unclear whether IL-18 plays a protective role during dengue infection (47) or is associated with adverse outcomes (43).…”

Restriction of HIV-1 Replication in Primary Macrophages by IL-12 and IL-18 through the Upregulation of SAMHD1

“…IL-12 appears to cooperate or act synergistically with IL-18 in the control of intracellular parasite infection of macrophages (7) or bridging innate and adaptive immunity (8)(9)(10). Notably, treatment of differentiated macrophages with IL-12/ IL-18 but not with M-CSF induces the production of IFN-g (5,6,11).…”