Participação da Fosfatidilinositol 3-quinase no modelo murino de infecção pelo dengue virus sorotipo 3

Abstract

Dengue is one of the most important mosquito-borne diseases affecting humans nowadays. It has become a great concern to public health system, given the incidence of the disease caused by dengue virus (DENV) has increased at an alarming rate in the last decades. Dengue transmission occurs through the bite of Aedes mosquitoes, especially Aedes aegypti. DENV infection is characterized by non-specific symptoms and treatment is only symptomatic. During the course of infection, immune system is activated and there is induction of a wide variety of antiviral and virus-supportive signaling pathways, among them, the Phosphoinositide 3-kinase (PI3K) pathway. PI3K activation catalyzes phosphorylation of inositol group in the phosphatidylinositol molecule, and present several functions in the body, such as proliferation and cell migration. The PI3Ks are classified into three classes, and the subject of this study is IB class. This class is composed solely by PI3K, which is related to inflammation. In order to study the role of this kinase in the pathogenesis of experimental dengue, we used adult wild type (WT) mice or mice deficient to PI3K (PI3K-/-). Mice were infected with dengue virus serotype 3 (DENV-3) and, after infection, we looked for PI3K pathway activation, through evaluation of AKT and NF-ß phosphorylation. In addition, lethality rates and dengue disease signals (hematocrit, platelets counts, production and release of cytokines and chemokine, neutrophil infiltration and analyses of liver damage and viral load) were evaluated after infection. It was observed that PI3K pathway is activated during infection, once AKT and NF-ß phosphorylation occurred. WT animals developed characteristic clinical signs of human disease, including thrombocytopenia, hemoconcentration, and tissue damage in liver, observed by histology and lesion score and high levels of hepatic transaminases in serum. In addition, also showed a higher production of cytokines and chemokine as well as a significant neutrophil infiltrate target organ disease such as liver and spleen. The animals PI3K-/- animals, in turn, showed no reduction in the number of circulating platelets and did not develop hemoconcentration. They also had lower levels of hepatic transaminases, lowest score of injury, minor changes in liver morphology, and lower neutrophil infiltration and reduced production of cytokines and chemokine when compared with infected WT mice. It is noteworthy also that animals PI3K-/- showed a significantly lower viral load in the liver, spleen and blood when compared to found in WT infected animals. In addition to the data presented, there was a reduced mortality rate in PI3K-/- animals, which allows us to infer that PI3K deficient mice are protected from serious illness.