Modulação farmacológica da via mTOR e seus efeitos na resposta imunometabólica durante infecção por Trypanosoma cruzi in vitro

Abstract

Chagas disease is an anthropozoonosis caused by the parasitic microeukaryote Trypanosoma cruzi. Considered a neglected neotropical disease by the World Health Organization, it is estimated that there are approximately 7 million carriers of the parasite worldwide. The fight against infection initially occurs through the mobilization and polarization of macrophages towards an M1 profile, that is, the development of a pro-inflammatory immune response. However, the parasite has strategies for evading the host's immune system that are based on inducing an anti-inflammatory response and polarizing macrophages to an M2 profile. Lipid droplets, modulated by the mTOR pathway, are involved in this process because they are cytoplasmic organelles classified as structural markers of macrophage activation. This study aims to describe the effect of modulating the mTOR signaling pathway, through pharmacological inhibition with rapamycin, on the inflammatory response of macrophages during in vitro infection by T. cruzi, observing the consequences on lipid metabolism, IL-10 release, mitochondrial activity, and parasite replication. In vitro infection with T. cruzi induced LD biogenesis, production of reactive oxygen species and anti-inflammatory cytokines, which favored parasite replication. However, pharmacological inhibition of the mTOR pathway promoted inhibition of LD formation, a tendency towards decreased anti-inflammatory cytokines, and favored the production of reactive nitrogen species that combated parasite replication. Furthermore, the infection caused membrane depolarization in mitochondria, but treatment was able to reverse this condition. Overall, the results obtained in this study show that modulation of the mTOR pathway interferes with LD biogenesis, reactive species production and membrane polarization, IL-10 cytokine synthesis, and parasite efficiency. This characterizes modulation of the pathway as a potential therapeutic target against Chagas disease.