Role of P2X7 receptor on activation and death of antigen presenting cells induced by T CD4+ cells of mice with acute and chronic malaria

Abstract

Understanding immunological mechanisms of malaria is extremely important for the development of vaccines and drugs that can give protection against this disease and its symptoms. Malaria is characterized by intense activation of the immune system that seems to contribute to protection against infection and to clinical manifestations related to disease. However, it is not clear which are the mechanisms responsible for the exacerbated immune response at acute phase and for the control of the disease at chronic phase. Currently, it has been shown that innate immunity is able to detect signals sent by damaged tissues and cells as ATP and uric acid. These danger signals seem to be important to promote inflammation regulation after damage or injuries done by pathogens, but also seem to contribute to activate immune responses. It is known that, at the moment of rupture of plasmodium-infected erythrocytes, significant amount of ATP is released. ATP is also released in the immune synapse, which occurs at interaction between T cells and antigen-presenting cells (APCs). Detection of extracellular ATP by immune system occurs through purinergic receptors, as the seven P2X receptors (P2X1-7R), present on the cell surface. Some studies show that ATP recognition by P2X7R in immune cells is important for cell activation and death. This is so because the P2X7R promotes inflammasome activation in macrophages and dendritic cells (DCs), and the subsequent release of cytokines, as interleukin-1², through a caspase-1-dependent process. Moreover, P2X7R is involved in the immune synapse between T cells and APCs, promoting calcium influx and favoring cell activation. Some cells, as regulatory T cells, have great amounts of ecto-ATPases on their surfaces that cleave extracellular ATP, regulating the immune response. Therefore, the main goal of this project is to evaluate the effects of P2X7R-mediated signaling on activation and death of APCs, what may occur as consequence of stimulation by CD4+ T cells from acute and chronic infection with Plasmodium chabaudi AS. The project is subdivided into two parts that have specific aims: 1) To compare in vitro the activation and death of DCs, macrophages and B cells from C57BL/6 mice and P2X7R knockout (P2X7R -/-) mice that are induced by CD4+ T cells from spleen of infected C57BL/6 mice, in the presence of parasitized erythrocytes. 2) To analyze if differences found in vitro can be also found in vivo in chimeric mice, in which part of immune cells are from C57BL/6 mice (that express green fluorescence protein - GFP) and part are from P2X7R /- mice. These goals are completely consistent with previous works that are being carried out by our research group that is supported by FAPESP and CNPq. Expected outcomes from this project will contribute to improve the understanding of malaria immunology.