Heme transport and utilization by Trypanosoma cruzi: Implications for Chagas disease

JULIA ALEJANDRA CRICCO

Tahoe City, CA, USA

Congreso; Trace Elements in Biology and Medicine FASEB meeting 2018; 2018

FASEB, Federation of American Societies for Experimental Biology

Chagas disease, or American trypanosomiasis, is caused by the protozoan parasite Trypanosoma cruzi. About 6 to 7 million people worldwide are estimated to be infected with T. cruzi, mainly in Latin America. However, in recent years it has been increasingly detected in the United States, Canada, many European and some Western Pacific countries, due to migration movements. In endemic regions, T. cruzi is mainly transmitted by the feces of the infected blood-sucking triatomine bugs, but it can also be transmitted by: consumption of food contaminated with T. cruzi; blood transfusion or organ transplants from infected donors; passage from an infected mother to her newborn during pregnancy or childbirth; and laboratory accidents.T. cruzi, like other trypanosomatids responsible for human diseases (T. brucei and Leishmania spp.), presents nutritional requirements for heme. They lack for heme synthesis route but present several heme-proteins involved in essential metabolic pathways like ergosterol and unsaturated fatty acid synthesis, and also respiratory chain complexes. We have demonstrated that T. cruzi presents the enzymes needed for heme A synthesis, cofactor only for Cytochrome c oxidase (CcO) (Buchensky, 2010) and also the relevance of this route. Our recent results have shown that an impairment on heme A synthesis causes a failure in CcO activity affecting the parasite?s proliferation and infectivity (Merli, 2017). These pieces of evidence reinforce the essentiality of heme transport, distribution and utilization by T. cruzi and related organisms. In this scenario the aims of our group are directed to elucidate how T. cruzi can: take heme from their hosts along its digenetic life cycle (blood sucking insect and mammals hosts); distribute heme inside cell; and controls heme intracellular concentration to avoid toxic effects. Recently, we have demonstrated that T. cruzi takes heme during the replicative life-cycle stages but not in the infective ones (Merli, 2016), suggesting that intracellular heme concentration is regulated by heme transport. Therefore, it is crucial to study the heme transporter -which has not been identified yet- and characterize its activity. We identified a gene encoding for the HRG protein of T. cruzi, TcHTE; it was localized in the flagellar pocket region of this parasite, where it is established that the trypanosomatids? transport proceeds (Merli, 2016). TcHTE can modulate the heme uptake and its expression (measured as mRNA) and accumulation (as protein) is regulated by intracellular heme levels. Based on our data, we postulate that TcHTE plays a crucial role in T. cruzi?s heme transport, regulating this activity, presumably being part or associated to the heme transporter.