Chagas disease, caused by the parasite Trypanosoma cruzi, 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 in vivo during T. cruzi 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-T. cruzi 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 T. cruzi infection in vitro 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 T. cruzi 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 T. cruzi, whereas epimastigotes and amastigotes displayed more resistance to this drug at the studied concentrations. Taken together, these data showed that this natural compound reduces T. cruzi 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.
Trypanosoma cruzi is the etiological agent of Chagas disease, which is endemic in Latin America. Ursolic acid (UA) is a natural pentacyclic triterpene which has been shown to reduce the peak of parasitemia in T. cruzi infected mice. Due to UA was described as an inducer of autophagy and having into account that our previous work established the protective role of this process on in vivo infections, we decided to study the possible involvement of UA in the elimination of parasites in macrophages and cardiac cells and its possible mechanism of action.To test this, we infected cells with T. cruzi for 24 hours, and then treated the samples with UA (5-10 µM) for different times. Our data showed that UA significantly decreased the amount of amastigotes compared to non-treated cells. We also studied the effect of UA on the autophagy response and other possible mechanisms of action we observed that UA induces the autophagy pathway, and that LC3, the marker of autophagy, is recruited around amastigotes, indicating xenophagy of these parasites. A cytotoxic effect was observed on T. cruzi trypomastigotes while epimastigotes displayed more resistance to this drug. Moreover, the production of ROS after 24 hours of treatment is increased on infected cells but, interestingly, UA does not have this effect on non-infected cells. We conclude that this natural compound promotes parasite death through induction of autophagy and other host cell responses.
Trypanosoma rangeli and T. cruzi are both parasitic unicellular species that infect humans. Unlike T. cruzi, the causative agent of Chagas disease, T. rangeli is an infective and non-pathogenic parasite for humans, but pathogenic for vectors from the Rhodnius genus. Because both species can coexist in different hosts and overlap their infective cycles but very little is known about the infection of T. rangeli in mammalian cells, we decided to characterize both the development of this parasite in cell culture and the effect of therapeutic agents with potential trypanocidal action on it. We found that T. rangeli exhibits a cycle of infection in Vero cells similar to that for T. cruzi and that the repurposed drug, 17-AAG, and the natural extract Artemisia sp. essential oil produce a toxic effect on epimastigotes showing a trypanocidal action from the fifth day of culture. Both treatments also affected the infection of trypomastigotes and reduced the capacity of replication of amastigotes of T. rangeli. Since T. cruzi / T. rangeli coinfection cases have been reported, the finding of drugs with potential activity against both species could be significant in the future. Furthermore, studies of susceptibility of both species to drugs could also help to know the different mechanisms of pathogenicity in humans displayed by T. cruzi that are absent in T. rangeli.
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