Cell death pathways in pathogenic trypanosomatids: lessons of (over)kill.

Especially in tropical and developing countries, the clinically relevant protozoa Trypanosoma cruzi (Chagas disease), Trypanosoma brucei (sleeping sickness) and Leishmania species (leishmaniasis) stand out and infect millions of people worldwide leading to critical social-economic implications. Low-income populations are mainly affected by these three illnesses that are neglected by the pharmaceutical industry. Current anti-trypanosomatid drugs present variable efficacy with remarkable side effects that almost lead to treatment discontinuation, justifying a continuous search for alternative compounds that interfere with essential and specific parasite pathways. In this scenario, the triggering of trypanosomatid cell death machinery emerges as a promising approach, although the exact mechanisms involved in unicellular eukaryotes are still unclear as well as the controversial biological importance of programmed cell death (PCD). In this review, the mechanisms of autophagy, apoptosis-like cell death and necrosis found in pathogenic trypanosomatids are discussed, as well as their roles in successful infection. Based on the published genomic and proteomic maps, the panel of trypanosomatid cell death molecules was constructed under different experimental conditions. The lack of PCD molecular regulators and executioners in these parasites up to now has led to cell death being classified as an unregulated process or incidental necrosis, despite all morphological evidence published. In this context, the participation of metacaspases in PCD was also not described, and these proteases play a crucial role in proliferation and differentiation processes. On the other hand, autophagic phenotype has been described in trypanosomatids under a great variety of stress conditions (drugs, starvation, among others) suggesting that this process is involved in the turnover of damaged structures in the protozoa and is not a cell death pathway. Death mechanisms of pathogenic trypanosomatids may be involved in pathogenesis, and the identification of parasite-specific regulators could represent a rational and attractive alternative target for drug development for these neglected diseases.