An Updated View of the Trypanosoma cruzi Life Cycle: Intervention Points for an Effective Treatment

Abstract

Chagas disease (CD) is a parasitic, systemic, chronic, and often fatal illness caused by infection with the protozoan Trypanosoma cruzi. The World Health Organization classifies CD as the most prevalent of poverty-promoting neglected tropical diseases, the most important parasitic one, and the third most infectious disease in Latin America. Currently, CD is a global public health issue that affects 6-8 million people. However, the current approved treatments are limited to two nitroheterocyclic drugs developed more than 50 years ago. Many efforts have been made in recent decades to find new therapies, but our limited understanding of the infection process, pathology development, and long-term nature of this disease has made it impossible to develop new drugs, effective treatment, or vaccines. This Review aims to provide a comprehensive update on our understanding of the current life cycle, new morphological forms, and genetic diversity of T. cruzi, as well as identify intervention points in the life cycle where new drugs and treatments could achieve a parasitic cure.

Keywords: Chagas disease; Trypanosoma cruzi; drug discovery; evolution model; genetic diversity; life cycle; morphological forms; target product profile; tropism.

Figure 1

Trypanosoma cruzi life cycle and key challenges for the development of effective treatments for Chagas disease. (1) Trypomastigotes migrate to the midgut and differentiate into epimastigotes. (2) Epimastigotes migrate to the hindgut and differentiate into metacyclic trypomastigotes. Abbreviations: CD, Chagas disease; PV, parasitophorous vacuole. The green and orange colors of the parasites represent two different strains and the stages at which genetic exchange occurs.

Figure 2

Timeline with the main events in the Chagas disease drug discovery.^,− Abbreviations: CD, Chagas disease; BTs, bloodstream trypomastigotes; DTUs, discrete typing units; NFX, nifurtimox; BZN, benznidazole; TPP, Target Product Profile; DNDi, Drugs for Neglected Diseases initiative; FPRTD, Fiocruz Program for Research and Technological Development; TDR, Tropical Diseases Research; WHO, World Health Organization; GHIT, Global Health Innovative Technology; ADMET, absorption, distribution, metabolism, excretion, and tolerability/toxicology; NITD, Norvartis Institute for Tropical Diseases.