Alves Érica Alessandra Rocha, de Miranda Marthina Gomes, Borges Tatiana Karla, Magalhães Kelly Grace, Muniz-Junqueira Maria Imaculada
Laboratory of Cellular Immunology, Area of Pathology, Faculty of Medicine, University of Brasilia, Brasilia, Distrito Federal, Brazil; Laboratory of Cellular and Molecular Immunology, René Rachou Research Center, Belo Horizonte, Minas Gerais, Brazil.
Laboratory of Cellular Immunology, Area of Pathology, Faculty of Medicine, University of Brasilia, Brasilia, Distrito Federal, Brazil.
Int Immunopharmacol. 2015 Feb;24(2):314-324. doi: 10.1016/j.intimp.2014.12.025. Epub 2014 Dec 26.
This study evaluated the influence of HIV protease inhibitors lopinavir/ritonavir (LPV/RTV) and atazanavir (ATV) on macrophage functions during their first interaction with Leishmania. Macrophages from BALB/c mice treated for 10days with LPV/RTV and ATV, infected or not in vitro with L. (L.) amazonensis, were used to investigate the effects of these drugs on infection index, leishmanicidal capacity, cytokine production and PPAR-γ and RelB expression. LPV/RTV and ATV treatments significantly increased the infection index and the percentage of Leishmania-infected macrophages compared to untreated infected macrophages. There was no correlated increase in the production of NO and H2O2 leishmanicidal molecules. Promastigotes derived from Leishmania-infected macrophages from LPV/RTV and ATV-treated BALB/c mice had an in vitro growth 45.1% and 56.4% higher in groups treated with LPV/RTV and ATV than with PBS in culture. ATV treatment reduced IL-12p70 and IL-10 secretion in Leishmania-infected macrophages, but had no effect on IL-23 and TNF production. LPV reduced IL-10 and had no effect on IL-12p70, TNF and IL-23 secretion. ATV treatment decreased PPAR-γ expression in Leishmania-infected macrophages compared to untreated infected macrophages. In addition, LPV/RTV, but not ATV, reduced RelB cytoplasm-to-nucleus translocation in Leishmania-infected macrophages. Results showed that LPV/RTV and ATV HIV protease inhibitors were able to modulate innate defense mechanisms against Leishmania via different intracellular pathways. Although HIV protease inhibitors are highly efficient to control the Human Immunodeficiency Virus, these drugs might also influence the course of leishmaniasis in HIV-Leishmania-co-infected individuals.
本研究评估了HIV蛋白酶抑制剂洛匹那韦/利托那韦（LPV/RTV）和阿扎那韦（ATV）在巨噬细胞与利什曼原虫首次相互作用期间对巨噬细胞功能的影响。使用经LPV/RTV和ATV处理10天的BALB/c小鼠的巨噬细胞，无论其在体外是否感染亚马逊利什曼原虫，来研究这些药物对感染指数、杀利什曼原虫能力、细胞因子产生以及PPAR-γ和RelB表达的影响。与未处理的感染巨噬细胞相比，LPV/RTV和ATV处理显著增加了感染指数以及利什曼原虫感染巨噬细胞的百分比。一氧化氮（NO）和过氧化氢（H₂O₂）等杀利什曼原虫分子的产生没有相应增加。来自经LPV/RTV和ATV处理的BALB/c小鼠的利什曼原虫感染巨噬细胞的前鞭毛体，在培养中用LPV/RTV和ATV处理的组比用磷酸盐缓冲液（PBS）处理的组体外生长分别高出45.1%和56.4%。ATV处理降低了利什曼原虫感染巨噬细胞中IL-12p70和IL-10的分泌，但对IL-23和肿瘤坏死因子（TNF）的产生没有影响。LPV降低了IL-10，对IL-12p70、TNF和IL-23的分泌没有影响。与未处理的感染巨噬细胞相比，ATV处理降低了利什曼原虫感染巨噬细胞中PPAR-γ的表达。此外，LPV/RTV而非ATV减少了利什曼原虫感染巨噬细胞中RelB从细胞质到细胞核的转位。结果表明，LPV/RTV和ATV这两种HIV蛋白酶抑制剂能够通过不同的细胞内途径调节针对利什曼原虫的固有防御机制。尽管HIV蛋白酶抑制剂在控制人类免疫缺陷病毒方面非常有效，但这些药物也可能影响HIV-利什曼原虫合并感染个体的利什曼病病程。
