Papel do IFN- e da iNOS na patogênese do dengue experimental

Abstract

Dengue is currently the most important mosquito-borne disease that affects humans and constitutes a serious world health problem. The lack of specific treatment and vaccine, and the incipient knowledge about pathogenesis contribute to the growing numbers of cases. A major limitation in the field of DENV research is the lack of animal models that mimic the human disease. Here, first, we aimed to create a newmodel of infection with DENV-3. The adaptation process allowed DENV-3 to multiply and cause disease in adult mice when given by intraperitoneal rout. The major findings after the inoculation of DENV-3 included increased vascular permeability, thrombocytopenia, increased systemic levels of cytokines (IL-6, TNF-, IFN- and CXCL-1), elevated levels of hepatic transaminases, greater tissue damage and inoculum-dependent lethality. In this work, we highlighted the cytokine IFN-, which has important functions in immunity to infectious agents. We evaluated the role played by IFN- and by one of its effectors molecules, nitric oxide, during the response to DENV-3 infection. For this, we used mice deficient in IFN- production (IFN--/-) and iNOS (iNOS-/-). After infection with DENV-3, wild type mice were able produce IFN- . Furthermore, IFN--/- presented higher lethality rates after DENV-3 infection if compared with their control counterparts. These animals presented increased tissuedamage and higher viral load in target organs. The roles of IL-12 and IL-18 cytokines were evaluated after infection with DENV-3 because this cytokines act in synergism to induce IFN- production. Indeed, IL-12p40 and IL-18-defficient mice presented higher lethality after DENV-3 infect, due to reduced hability to produce IFN-g and consequent increased viral loads. Finally, despite the high levels of IFN- produced duringinfection, iNOS-/- mice seemed to be unable to control DENV-3 replication, had higher tissue damage and died. Then, we conclude that IFN--induced NO production is an important pathway during response to dengue virus infection. In addition, IL-12 and IL- 18 appear to control IFN- production during DENV-3 infection. In the absence of these molecules, there is reduced ability of the host to control viral replication, resulting inincreased tissue damage and death of the infected animals. . Strategies capable to enhance production of these molecules may result in benefits during the control of primary infection by DENV-3.