Induced pluripotent stem cell-derived human macrophages as an infection model for Trypanosoma cruzi

Abstract

Chagas disease, caused by the parasite Trypanosoma cruzi, affects millions of people globally. Unfortunately, the available treatment options, especially for the chronic stage of the disease, are suboptimal. Given the chronic nature of the disease and the elusive nature of the parasite, there is a high need for new and safer drugs that deliver sterile cure. Posaconazole was a promising lead in the drug discovery pipeline but ultimately failed in clinical trials due to patient relapses. This failure illustrates the need for a drug screening assay that can predict sterile cure by assessing recrudescence after treatment. Here, we used human induced pluripotent stem cell (iPSC)-derived macrophages (iMACs) as host cells for T. cruzi. The iMACs were highly susceptible to infection by the parasites. By combining red fluorescent protein (RFP)-expressing iMACs with mNeonGreen-expressing T. cruzi, we were able to monitor the dynamics of the infection through live cell imaging. The activity of the compounds benznidazole and posaconazole was consistent with the results of an established infection system using mouse primary macrophages. The post-mitotic nature of iMACs makes them suitable host cells for long-term assays needed to assess recrudescence of parasites. Moreover, their human origin, stable genetic background, and capacity for genetic modification make the iMACs excellent host cells for studying host-pathogen interaction. Author summaryThe parasite Trypanosoma cruzi, the causative agent of Chagas disease, is a global health concern affecting millions each year. Infection with T. cruzi can cause chronic disease, often remaining asymptomatic for decades before resulting in severe cardiac or gastro-intestinal pathologies. To date, only benznidazole and nifurtimox are used for treatment of the infection, but both drugs are suboptimal for curing the chronic stage. Posaconazole showed great promise in preclinical studies but failed to achieve sterile cure in clinical trials, causing patient relapses. These disappointing results underline the need for drug screening assays able to predict sterile cure by evaluating recrudescence post-treatment. We used human induced pluripotent stem cell derived macrophages as host cells for T. cruzi and testing of trypanocidal compounds. This model can be used for long-term in vitro screening assays to find new drug candidates against Chagas disease. The human origin of these cells combined with the possibility of upscaling their production make them great host cells for drug screening campaigns.