Avaliação da atividade imunomoduladora da quercetina na infecção de monócitos por Leishmania (Leishmania) infantum

Abstract

Leishmaniasis is an infectious-parasitic disease that affects various types of mammals. Approximately 1.2 million new cases are reported annually in humans, and primarily concentrated in vulnerable populations living in high-risk areas. The disease presents different clinical manifestations, ranging from mild forms to highly debilitating conditions. Visceral leishmaniasis is the most severe form of the disease, with mortality rates exceeding 90% if left untreated. In the context of disease cure, numerous studies have been dedicated to developing new therapies, as conventional treatments exhibit high toxicity levels, resistance issues, and recurrence. Among the novel therapeutic approaches for leishmaniasis, the combination of conventional drugs with natural products has emerged as one of the most promising strategies. Quercetin is a flavonoid found in a wide variety of plants, and its antioxidant, pro-oxidant, immunomodulatory, anti-tumor, antibacterial, antifungal, and antiprotozoal activities have been extensively studied. Based on this, the present study aimed to evaluate the biological activity of quercetin and its combination with Amphotericin B against promastigote cultures of Leishmania (Leishmania) infantum and in the context of human monocyte infection. To achieve this, we treated promastigote cultures, erythrocytes, and PBMCs—both uninfected and infected—with multiple concentrations of quercetin and AmB, either alone or in combination. We then assessed: (1) the isolated and synergistic activity of the compounds in parasite death using the MTT assay; (2) the cytotoxicity of the compounds on human cells; (3) the influence of the compounds on the infection rate; (4) the production of Reactive Oxygen Species (ROS); (5) Nitric Oxide (NO) production in monocytes; (6) nitrite production in PBMCs exposed to L. infantum via the Griess reaction; and finally, (7) the modulation of cytokine profiles in PBMCs with and without L. infantum infection. Our results demonstrated that quercetin exhibited anti-promastigote activity, and its combination with AmB enhanced parasite death, indicating synergy between the molecules. Additionally, quercetin reduced monocyte infection rates and positively modulated ROS production, although AmB did not participate in these mechanisms. Furthermore, none of the tested conditions regulated NO production, but the combination of compounds showed a tendency to increase NO levels in infected cells. Finally, quercetin reduced IL-6 and IL-17 production but did not alter IFN-γ, IL-10, or IL-12 expression, whereas AmB reduced IL-6 levels but did not affect IFN-γ, IL-10, IL-12, or IL-17 expression. Therefore, our data suggest that quercetin acts as an immune response modulator and may be used synergistically with AmB to enhance the healing process.