Between Armour and Weapons — Cell Death Mechanisms in Trypanosomatid Parasites

Abstract

Among the pathogenic protozoa, trypanosomatids stand out due to their medical and economic impact, especially for low-income populations in tropical countries. Together, sleeping sickness, Chagas disease and leishmaniasis affect millions of humans and animals worldwide, yet are neglected by the pharmaceutical industry. The current drugs for trypanosomatid infections are limited and unsatisfactory, with severe side effects leading to reduced quality of life and, in several instances, to the abandonment of treatment. An intense search for alternative compounds has been performed, aiming at specific parasite targets by cellular, molecular and biochemical approaches. One interesting strategy could be interference with the protozoan cell death pathways. However, these pathways are poorly understood in unicellular eukaryotes, with the controversial existence and uncertain biological relevance of programmed cell death (PCD). This chapter will discuss apoptosis-like and autophagic cell death and necrosis in Trypanosoma brucei, Trypanosoma cruzi and Leishmania sp. and the possible implications of these pathways for the parasite life cycle and infection persistence. It will also revisit the genomic and proteomic metadata of these trypanosomatids in the literature to rebuild the map of cell death proteins expressed under different conditions. The interaction of leading candidates with parasite-specific molecules, especially with enzymes that regulate key steps in the cell death process, is a rational and attractive alternative for drug development for these neglected diseases.

TrypanocidalActivity of Natural Sesquiterpenoids Involves Mitochondrial Dysfunction, ROS Production and Autophagic Phenotype in Trypanosoma cruzi

“…On the other hand, the increase in the number of labelled parasites was only induced by Pgd, indicating that only this compound promotes an increase in both the percentage of epimastigotes producing ROS and the quantity of reactive species generated. Lipid peroxidation is a classical consequence of the increase in cellular ROS amounts, which can also lead to plasma membrane rupture [ 15 ]. Our results showed an increase in plasma membrane permeability and ROS production only after incubation with Pgd, which is indicative of necrosis.…”

“…Another biological pathway that has been associated with the mechanisms of action of anti-trypanosome drugs is autophagy [ 13 , 14 ]. The autophagy pathway is a pivotal degradation process in the recycling of cellular structures, which is also important in trypanosomatids [ 15 ]. The loss of autophagic balance could represent a critical point for the development of chemotherapeutic alternatives.…”

Evaluation of antitrypanosomal properties and apoptotic effects of ochrolifuanine from Dyera costulata (Miq.) Hook.f against Trypanosoma brucei brucei

“…Over the years, much evidence has been accumulated to describe morphological and biochemical events displayed during the death of trypanosomatids which share certain characteristics with mammalian apoptosis phenomena (Debrabant et al, 2003;Fernandez-Presas et al, 2010;Menna-Barreto & Castro, 2015). The apoptotic features shown by these kinetoplastid parasites include DNA fragmentation, depolarization of mitochondrial membrane potential, protease activation, membrane blebbing, the exposure of phosphatidylserine in the outer leaflet of the plasma membrane, chromatin condensation and cytochrome c release.…”

In Silico, In Vitro, and Pharmacokinetic Studies of UBMC-4, a Potential Novel Compound for Treating against Trypanosoma cruzi

“…Trypomastigotes may be prone to activate constant mechanisms of tolerance to cellular stress; therefore, UBMC-4 might act regardless of the parasites being subjected to nutritional stress or not. The second is a hypothesis that has already been proven in different studies where trypomastigotes are shown to be highly autophagic, a process known to have a dual function inhibiting or promoting apoptosis-mediated cell death processes [37].…”