Mecanismos efetores de monócitos na malária humana causada pelo Plasmodium vivax

Abstract

In most parasitic infections, there is a relationship between the etiologic agent and the host's immune system, whose balance, if altered, can influence the host’s susceptibility and, therefore, the prognosis of the disease. During malaria, Plasmodium spp. triggers the production of high levels of inflammatory cytokines that are both essential for the control of the parasite and responsible for the symptoms observed during the disease. Our group demonstrated that monocytes play an important role in host defense against Plasmodium vivax infection and represent the main source of inflammatory cytokines and reactive oxygen species. In order to modulate inflammation, anti-inflammatory cytokines, such as IL-10, are also produced. Studies suggested that different clinical presentations of malaria are strongly associated with an imbalance in inflammatory and anti-inflammatory cytokines production. Based on that, despite advances in our understanding of the involvement of protective and immunopathological immunity, little is known about maintaining this balance during malaria. The present study demonstrates that during P. vivax infection monocyte metabolism is altered with mitochondria playing a major function in this switch. This transition involves a reprograming in monocyte metabolism in which the cells increase glucose uptake and produce ATP via glycolysis instead of via oxidative phosphorylation (OXPHOS). Morevover, the above changes are associated with altered mitochondrial membrane potential leading to an increase in mROS instead of ATP production, which can be involved in parasite control since these organells are able to migrate to the phagolysosome containing the Pv-RET and produced mROS. On the other hand, monocytes also participate in the modulation of this inflammatory response during malaria. They express higher levels of ectonucleotidases than other leukocytes, indicating their important role in extracellular ATP modulation and consequently in adenosine production. Despite plasmatic levels of adenosine were decreased in patients experiencing acute malaria caused by P. vivax, the same patients display an increased expression of P1 purinergic receptors on monocyte subsets. In addition, adenosine increases IL-10 and decreases TNF production by monocytes. Importantly, this effect was completely abolished with the blockage of A2a receptor. All together our data show that monocytes have a dual role during malaria caused by P. vivax, simultaneously attempting to control the infection and the potential deleterious inflammatory response.