ABSTRACT
Chagas disease (ChD) is one of the most neglected tropical diseases, with cardiomyopathy being the main cause of death in Trypanosoma cruzi-infected patients. As the parasite actively replicates in cardiomyocytes (CMs), the heart remains a key target organ in the pathogenesis of ChD. Here we modeled ChD using human induced pluripotent stem cell-derived CMs (iPSC-CMs) to understand the complex interplay between the parasite and host cells. We showed that iPSC-CMs can get infected with the T. cruzi Y strain and that all parasite cycle stages can be identified in our model system. Importantly, characterization of T. cruzi-infected iPSC-CMs showed significant changes in their gene expression profile, cell contractility, and distribution of key cardiac markers. Moreover, these infected iPSC-CMs exhibited a pro-inflammatory profile as indicated by significantly elevated cytokine levels and cell-trafficking regulators. We believe our iPSC-CM model is a valuable platform to explore new treatment strategies for ChD.
Subject(s)
Chagas Cardiomyopathy/metabolism , Induced Pluripotent Stem Cells , Models, Biological , Myocytes, Cardiac , Trypanosoma cruzi/metabolism , Chagas Cardiomyopathy/pathology , Chagas Cardiomyopathy/therapy , Humans , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/parasitology , Induced Pluripotent Stem Cells/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/parasitology , Myocytes, Cardiac/pathologyABSTRACT
Possibilities to study the biology of human protozoan parasites and their interaction with the host remain severely limited, either because of non-existent or inappropriate animal models or because parasites cannot even be cultured in vitro due to strict human-host specificity or physiology. Here we discuss the prospects of using induced pluripotent stem cell (iPSC)-derived culture systems including organoids as a strategy to address many of these experimental bottlenecks. iPSCs already allow the generation of differentiated cell cultures for many human organs, and these cells and derivatives are amenable to reverse genetics in combination with advanced tools for genetic manipulation. We present examples of blood, neuron, liver, and intestine-dwelling protozoa, i.e. Plasmodium falciparum, Toxoplasma gondii and Giardia duodenalis, where iPSCs or organoids would allow addressing questions of cell and developmental biology, immunology, and pharmacology in unprecedented ways. Starting points and resources for iPSC experimentation are briefly discussed.
