Laboratório de Imunoparasitologia, Departamento de Ciências Biológicas, Instituto de Ciências Exatas e Biológicas/NUPEB, Universidade Federal de Ouro Preto, Campus do Morro do Cruzeiro, 35400-000 Ouro Preto, MG, Brazil.
Departamento de Bioquímica e Biologia Molecular, Laboratório de Infectologia Molecular Animal, Instituto de Biotecnologia Aplicada à Agropecuária/BIOAGRO, Universidade Federal de Viçosa, 36570-900 Viçosa, MG, Brazil.
Microbes Infect. 2015 Apr;17(4):295-303. doi: 10.1016/j.micinf.2014.12.009. Epub 2014 Dec 30.
Leishmania amazonensis, the causal agent of diffuse cutaneous leishmaniasis, is known for its ability to modulate the host immune response. Because a relationship between ectonucleotidase activity and the ability of Leishmania to generate injury in C57BL/6 mice has been demonstrated, in this study we evaluated the involvement of ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) activity of L. amazonensis in the process of infection of J774-macrophages. Our results show that high-activity parasites show increased survival rate in LPS/IFN-γ-activated cells, by inhibiting the host-cell NO production. Conversely, inhibition of E-NTPDase activity reduces the parasite survival rates, an effect associated with increased macrophage NO production. E-NTPDase activity generates substrate for the production of extracellular adenosine, which binds to A2B receptors and reduces IL-12 and TNF-α produced by activated macrophages, thus inhibiting NO production. These results indicate that E-NTPDase activity is important for survival of L. amazonensis within macrophages, showing the role of the enzyme in modulating macrophage response and lower NO production, which ultimately favors infection. Our results point to a new mechanism of L. amazonensis infection that may pave the way for the development of new treatments for this neglected disease.
亚马逊利什曼原虫是皮肤利什曼病的病原体，其能够调节宿主免疫反应的能力是众所周知的。因为已经证明了核苷酸酶活性与利什曼原虫在 C57BL/6 小鼠中产生损伤的能力之间存在关系，所以在这项研究中，我们评估了亚马逊利什曼原虫的外核苷酸三磷酸二磷酸水解酶（E-NTPDase）活性在感染 J774-巨噬细胞过程中的参与。我们的结果表明，高活性寄生虫在 LPS/IFN-γ 激活的细胞中表现出更高的存活率，通过抑制宿主细胞的 NO 产生。相反，抑制 E-NTPDase 活性会降低寄生虫的存活率，这与巨噬细胞中 NO 产生增加有关。E-NTPDase 活性产生细胞外腺苷的底物，该物质与 A2B 受体结合，减少激活的巨噬细胞中产生的 IL-12 和 TNF-α，从而抑制 NO 的产生。这些结果表明，E-NTPDase 活性对于利什曼原虫在巨噬细胞内的存活至关重要，表明该酶在调节巨噬细胞反应和降低 NO 产生方面的作用，这最终有利于感染。我们的研究结果表明了一种新的亚马逊利什曼原虫感染机制，这可能为治疗这种被忽视的疾病开辟新的治疗途径。
