Trypanosoma cruzi, the causative agent of Chagas disease, depends on host-derived nutrients, including heme and transition metal ions like copper and iron, for survival. Unlike most eukaryotes, T. cruzi lacks heme B biosynthesis but imports and converts it to heme A for incorporation into cytochrome c oxidase (COX) (1), a key respiratory complex requiring both heme A and copper ions (Cu). While the parasite lacks canonical Cu transporters (e.g., Ctr1/3, DMT-1) or cytosolic Cu chaperones, it retains conserved mitochondrial Cu-handling proteins and Cu P-type ATPases (TcCuATPase).
We aim to elucidate the molecular mechanisms by which T. cruzi acquires heme and Cu from its hosts, regulates their intracellular trafficking, and mitigates cytotoxicity. By integrating biochemical, molecular and genetic, also microscopy and spectroscopic techniques, we seek to identify key pathways involved in metal ions homeostasis, specifically Cu, offering insights into parasite survival and potential therapeutic targets. We demonstrated that Cu is an essential cofactor along T. cruzi life cycle, also, that changes in intracellular Cu availability (presumably Cu-labile) negatively affect parasite proliferation. This finding points Cu homeostasis as an attractive target to control parasite proliferation and infectivity. In addition, we identified candidate genes (including TcCuATPase, TcFR [ferric reductase], and TcIT [iron transporter]) involved in Cu transport and homeostasis. Under Cu stress, we observed changes in their expression profile, supporting their role in Cu distribution and homeostasis. Our findings reveal a non-canonical Cu transport pathway in T. cruzi, proposing a model where conserved (TcCuATPase) and repurposed (TcFR, TcIT) proteins coordinate Cu handling (2).
This work advances understanding of parasite metallobiology and highlights potential targets for disrupting T. cruzi proliferation and infectivity.