Laboratorio de biología de Trypanosoma cruzi y la célula hospedadora, Instituto de Histología y Embriología de Mendoza, Instituto de Histología y Embriología de Mendoza-Consejo Nacional de Investigaciones Científicas y Técnicas (IHEM-CONICET)-Universidad Nacional de Cuyo, Mendoza, Argentina.
Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina.
Front Cell Infect Microbiol. 2022 Jul 8;12:919096. doi: 10.3389/fcimb.2022.919096. eCollection 2022.
Chagas disease, caused by the parasite , is an infectious illness endemic to Latin America and still lacks an effective treatment for the chronic stage. In a previous study in our laboratory, we established the protective role of host autophagy during infection in mice and proposed this process as one of the mechanisms involved in the innate immune response against this parasite. In the search for an autophagy inducer that increases the anti- response in the host, we found ursolic acid (UA), a natural pentacyclic triterpene with many biological actions including autophagy induction. The aim of this work was to study the effect of UA on infection in the late infection stage, when the nests of intracellular parasites are forming, in both macrophages and cardiac cells. To test this effect, the cells were infected with for 24 h and then treated with UA (5-10 µM). The data showed that UA significantly decreased the number of amastigotes found in infected cells in comparison with non-treated cells. UA also induced the autophagy response in both macrophages and cardiac cells under the studied conditions, and the inhibition of this pathway during UA treatment restored the level of infection. Interestingly, LC3 protein, the main marker of autophagy, was recruited around amastigotes and the acidic probe LysoTracker localized with them, two key features of xenophagy. A direct cytotoxic effect of UA was also found on trypomastigotes of , whereas epimastigotes and amastigotes displayed more resistance to this drug at the studied concentrations. Taken together, these data showed that this natural compound reduces infection in the later stages by promoting parasite damage through the induction of autophagy. This action, in addition to the effect of this compound on trypomastigotes, points to UA as an interesting lead for Chagas disease treatment in the future.
恰加斯病由寄生虫引起，是拉丁美洲流行的传染病，目前仍缺乏针对慢性期的有效治疗方法。在我们实验室的先前研究中，我们确立了宿主自噬在感染期间的保护作用，并提出该过程是宿主固有免疫反应的机制之一。在寻找一种能够增加宿主抗反应的自噬诱导剂的过程中，我们发现了熊果酸（UA），这是一种天然五环三萜，具有许多生物学作用，包括诱导自噬。本研究旨在研究 UA 在感染后期（即细胞内寄生虫巢形成时）对感染的影响，包括巨噬细胞和心肌细胞。为了测试这种效果，细胞先被感染 24 小时，然后用 UA（5-10 µM）处理。结果显示，与未经处理的细胞相比，UA 显著降低了感染细胞中发现的无鞭毛体数量。UA 还在研究条件下诱导了巨噬细胞和心肌细胞的自噬反应，而在 UA 处理期间抑制该途径会恢复感染水平。有趣的是，LC3 蛋白（自噬的主要标志物）被募集到无鞭毛体周围，酸性探针 LysoTracker 与它们一起定位，这是胞质溶酶体吞噬的两个关键特征。还发现 UA 对 的锥虫也有直接的细胞毒性作用，而在研究浓度下，动基体和无鞭毛体对这种药物的抵抗力更强。总之，这些数据表明，这种天然化合物通过诱导自噬促进寄生虫损伤，从而减少感染后期的感染。这种作用，除了该化合物对锥虫的作用外，表明 UA 是未来治疗恰加斯病的一个有前途的先导化合物。
