Análise funcional da 7-desidrocolesterol redutase na resposta imune durante a infecção por Leishmania spp.

Abstract

Leishmaniasis is caused by protozoa of the genus Leishmania spp. and is a neglected parasitic disease with a broad clinical spectrum, whose treatments are toxic and present failures and resistance. Leishmania braziliensis (Lb) and Leishmania amazonensis (La) are highly prevalent species in Brazil. Cholesterol metabolism affects immune responses. 7-dehydrocholesterol reductase (DHCR7) converts 7-dehydrocholesterol (7-DHC) into cholesterol and this enzyme regulates the polarization of macrophages towards the M2 profile. The main objective is to evaluate the role of DHCR7 in the immune response and in the control of Leishmania spp. infections. Human macrophages derived from THP-1 cells were infected with L. amazonensis or L. braziliensis expressing green fluorescent protein (GFP) for 24 h and treated with pharmacological inhibitors of DHCR7 (tamoxifen and AY9944) for an additional 24 h for flow cytometric analysis. Public transcriptome analysis demonstrated that DHCR7 is less expressed in lesions from patients with cutaneous leishmaniasis compared with skin from healthy controls. DHCR7 is negatively correlated with the expression of pro-inflammatory molecules in lesions from patients. Inhibition of DHCR7 reduced infection by both Leishmania species in human macrophages. Furthermore, DHCR7 inhibitors promoted an increase in the production of reactive oxygen intermediates (ROS) and in the production of TNF and IL-1β by human macrophages infected with Leishmania spp, assessed by CBA in the supernatant. These data suggest that DHCR7 inhibitors control Leishmania spp. infection and pave the way for new therapeutic approaches for this neglected disease.