Ativação pela MYD88 aumenta níveis de quinurenina e modula resposta de células T em malária

Abstract

Malaria remains one of the world's worst health problems. In Brazil more than 90% of the infections are caused by Plasmodium vivax. Recent evidence demonstrates an increase in IL-10 and T regulatory cells (Tregs, CD4+CD25+CD127-Foxp3+) in Plasmodium infections in humans and mice. However, the mechanisms that lead to this increase are poorly understood. In view of this, our goal was to understand the role of the innate immune response and the factors that lead to increase in Tregs. We observed elevated level of kynurenine (KYU) and indoleamine 2,3-dioxygenase (IDO) activity, measured by HPLC and an increase in IL-6, IL-10 and IFN-y quantified by CBA in patients infected with P. Vivax. In vitro stimulation of PBMCs by extract of P.vivax infected-erythrocytes (Pv) increased IDO-1 expression in CD14+ cells that was accompanied by an increase in kynurenine and, cytokines IL-6, IL-10, TNF-a and IFN-y. In addition, we observed by flow cytometry a reduction in the activation of T cells and an increase in frequency of Tregs upon Pv stimulation. The increase of kynurenine was blocked by addition of IDO and MyD88 inhibitors. Blocking IDO and MyD88, we also observed a reduction in kynurenine, cytokines and Treg cells and an increase in activated CD4+T cells. In conclusion, we demonstrate for the first time that increased IDO activity increases frequency of Tregs, which suppresses T effector cell response in malaria.