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.
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.
Immunopharmacology, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Caio T
CT
Fagundes
Vivian V
VV
Costa
Daniel
D
Cisalpino
Flávio A
FA
Amaral
Patrícia R S
PR
Souza
Rafael S
RS
Souza
Bernhard
B
Ryffel
Leda Q
LQ
Vieira
Tarcília A
TA
Silva
Alena
A
Atrasheuskaya
George
G
Ignatyev
Lirlândia P
LP
Sousa
Danielle G
DG
Souza
Mauro M
MM
Teixeira
D000818:Animals; D003715:Dengue / Q000276:immunology* / Q000473:pathology; D003716:Dengue Virus / Q000276:immunology*; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D020382:Interleukin-18 / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D012720:Severity of Illness Index; D016019:Survival Analysis
D020382:Interleukin-18; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma