The regulation of autophagy differentially affects Trypanosoma cruzi metacyclogenesis

Abstract

Autophagy is a cellular process required for the removal of aged organelles and cytosolic components through lysosomal degradation. All types of eukaryotic cells from yeasts to mammalian cells have the machinery to activate autophagy as a result of many physiological and pathological situations. The most frequent stimulus of autophagy is starvation and the result, in this case, is the fast generation of utilizable food (e.g. amino acids and basic nutrients) to maintain the vital biological processes. In some organisms, starvation also triggers other associated processes such as differentiation. The protozoan parasite Trypanosoma cruzi undergoes a series of differentiation processes throughout its complex life cycle. Although not all autophagic genes have been identified in the T. cruzi genome, previous works have demonstrated the presence of essential autophagic-related proteins. Under starvation conditions, TcAtg8, which is the parasite homolog of Atg8/LC3 in other organisms, is located in autophagosome-like vesicles. In this work, we have characterized the autophagic pathway during T. cruzi differentiation from the epimastigote to metacyclic trypomastigote form, a process called metacyclogenesis. We demonstrated that autophagy is stimulated during metacyclogenesis and that the induction of autophagy promotes this process. Moreover, with exception of bafilomycin, other classical autophagy modulators have similar effects on T. cruzi autophagy. We also showed that spermidine and related polyamines can positively regulate parasite autophagy and differentiation. We concluded that both polyamine metabolism and autophagy are key processes during T. cruzi metacyclogenesis that could be exploited as drug targets to avoid the parasite cycle progression.

Author summary

In spite of its old discovery, more than one hundred years ago, Trypanosoma cruzi, the causative agent of Chagas’ disease, is still prevalent in the world, infecting more than 6 million people mostly in Latin America, where this illness is endemic. Only two approved drugs, benznidazole and nifurtimox, are currently used for the treatment of Chagas’ disease. Although efficient for the acute phase, they are poorly effective in the chronic period of the disease and they cause many undesirable side effects. There is an urgent need for therapeutic alternatives. To this end, identifying and validating novel molecular targets is critically relevant. This study describes the effect of different inhibitors on the T. cruzi autophagic pathway, a process required for parasite differentiation. Herein, we demonstrate that the regulation of parasite autophagy exhibits similarities and differences with host cell autophagy. Our study provides new insights that could be used to avoid T. cruzi cycle progression in both insect and mammalian hosts.