Quercetin enhances amphotericin B activity and regulates ROS and cytokine production in human monocytes infected by Leishmania infantum

Leishmania infantum, the main causative agent of zoonotic visceral leishmaniasis, persists and proliferates within host monocytes and macrophages. Numerous studies have focused on developing innovative therapies, as conventional treatments are hampered by high toxicity, drug resistance, and relapse. In recent decades, anti-leishmanial immunotherapy - aimed at triggering or modulating the host's immune response - has gained momentum, with various immunomodulators being tested in experimental and clinical settings. However, achieving effective immunotherapy remains challenging, as it requires a delicate balance between enhancing protective, parasite-specific immune responses and avoiding harmful hyperinflammation. In this context, we evaluated quercetin, a natural flavonoid with reported immunomodulatory properties, alone and in combination with Amphotericin B (AmB), against Leishmania infantum promastigotes and during human monocyte infection. Infected and non-infected PBMCs were assessed for parasite viability and cytotoxicity; monocyte infection rates, reactive oxygen species (ROS), nitric oxide (NO) production, and cytokine profiles. Quercetin showed significant anti-promastigote activity and, in combination with AmB, enhanced parasite death, indicating synergistic effects. It also reduced monocyte infection rates, enhanced ROS production, and downregulated levels of IL-6, IL-10, and IL-17, without altering NO production. These findings support the concept of quercetin as a dual-action agent, exerting direct anti-leishmanial effects while fine-tuning the host immune response. By promoting beneficial immunological pathways and dampening potentially deleterious cytokines, quercetin exemplifies the "trapeze act" of immunotherapy, suggesting its potential as an adjuvant to conventional chemotherapy in visceral leishmaniasis.