Caracterização da resposta imunometabólica frente a infecção por Leishmania amazonensis e Leishmania braziliensis em macrófagos de camundongos BALB/C

Abstract

INTRODUCTION: Leishmaniasis is a neglected tropical disease caused by protozoa of the genus Leishmania and represents a serious public health problem. These parasites infect cells of the innate immune system, particularly macrophages, and possess the ability to modulate cellular metabolism during infection, favoring their survival. The present study investigates the metabolic alterations induced by Leishmania spp. in the energy metabolism of macrophages, based on the hypothesis that infection promotes mitochondrial dysfunction, contributing to parasite persistence in the host. We emphasize the relevance of this study in advancing the understanding of immune responses and developing new therapeutic strategies and potential targets for intervention. OBJECTIVE: To evaluate the metabolic profile of macrophages derived from the BALB/c lineage infected with L. amazonensis and L. braziliensis. MATERIALS AND METHODS: Bone marrow-derived macrophages were obtained from BALB/c mice. Subsequently, these cells were treated with metabolic inhibitors and infected with L. amazonensis and L. braziliensis, evaluating the parasite burden and infection rate. Additionally, we characterized the metabolism of infected macrophages in real time using Seahorse assays. The production of cellular reactive oxygen species (ROS) was measured using the “CellROX” probe, and mitochondrial reactive oxygen species (mtROS) were measured using the “MitoSOX” probe. RESULTS: Murine macrophages treated with antimycin A and FCCP, mitochondrial metabolism inhibitory drugs, showed a reduction in parasite burden and infection rate, highlighting the importance of mitochondrial metabolism for parasite survival. Although infection does not increase basal respiration in macrophages, it elevates oxygen consumption parameters and reduces ATP production, suggesting mitochondrial dysfunction. Pre-treatment with fatty acid synthesis inhibitors increases cellular ROS, whereas pre-treatment with glycolysis inhibitors reduces mtROS, revealing critical interactions between host cell metabolism and parasite survival. CONCLUSION: Our study suggests that infection with L. amazonensis and L. braziliensis interferes with host metabolism, particularly mitochondrial metabolism. We also highlight the importance of lipid metabolism, especially in infection by L. braziliensis. This work reinforces the idea that host mitochondrial, and lipid metabolism are critical factors for parasite survival, indicating that metabolism-targeted therapies could offer new strategies for leishmaniasis control