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

Area of Science:

• Parasitology
• Molecular Biology
• Drug Discovery

Background:

• Trypanosomatid parasites (Trypanosoma cruzi, Trypanosoma brucei, Leishmania species) cause neglected tropical diseases affecting millions globally.
• Current treatments for these diseases have limited efficacy and significant side effects, necessitating novel therapeutic strategies.
• The mechanisms and importance of programmed cell death (PCD) in these unicellular eukaryotes remain poorly understood.

Purpose of the Study:

• To review the known mechanisms of cell death, including autophagy, apoptosis-like cell death, and necrosis, in pathogenic trypanosomatids.
• To discuss the potential roles of these cell death pathways in parasite pathogenesis and infection.
• To identify parasite-specific molecular regulators as potential drug targets for neglected trypanosomatid diseases.

Main Methods:

• Literature review of published genomic and proteomic data on trypanosomatid cell death molecules.
• Analysis of experimental conditions influencing cell death pathways.
• Discussion of morphological evidence and molecular mechanisms of cell death.

Main Results:

• Despite morphological evidence, trypanosomatid cell death is often classified as unregulated or incidental necrosis due to a lack of identified molecular regulators and executioners.
• Autophagy is observed under various stress conditions, suggesting a role in cellular maintenance rather than a direct cell death pathway.
• Metacaspases, crucial for parasite proliferation and differentiation, have not been implicated in PCD.

Conclusions:

• Cell death mechanisms in pathogenic trypanosomatids are complex and may contribute to disease pathogenesis.
• Identifying parasite-specific regulators of cell death offers a rational approach for developing new drugs against neglected trypanosomatid infections.
• Targeting these pathways could lead to more effective treatments with fewer side effects.