Homeostasis of Metal Cofactors in Trypanosomatids


Trypanosomatids are single-celled parasites, some of them are responsible for various diseases in humans and animals such as Trypanosoma cruzi that causes Chagas disease. According to the World Health Organization, it is one of the 17 Neglected Tropical Diseases that is endemic in Latin America. In non-endemic developed countries, the number of patients has increased due to increased migration. There are currently between 5 and 6 million people infected, of which less than 1% receive treatment, and it is estimated to cause 7,000 deaths per year.These parasites have a complex life cycle alternating between an insect vector responsible for their transmission and a mammalian host that can develop the disease. During this cycle they must adapt to different environments with different availability of nutrients. In the laboratory we study the transport and homeostasis processes of essential cofactors and metabolites in T. cruzi.

Research Lines

Heme transport, distribution, and metabolism in Trypanosoma cruzi

Trypanosoma cruzi has nutritional requirements for essential metabolites, where heme group other cofactors such as iron, copper, calcium, etc. metal ions are included. This parasite lacks a route for heme synthesis, then it must guarantee the acquisition, storage, and correct use of heme throughout its life cycle. This characteristic is shared by other trypanosomatids responsible for diseases in humans such as T. brucei, Leishmania spp., and other parasites. In our laboratory, we study the molecular mechanisms developed by T. cruzi that govern heme homeostasis. The identification of transport proteins and/or chaperones that participate in these processes, and their subsequent functional and structural characterization, will generate relevant information on essential processes for the proliferation and survival of the parasite. This knowledge will validate this pathway as a possible chemotherapeutic target for the design of drugs for new treatments against Chagas disease.

Copper ions homeostasis in Trypanosoma cruzi

Trypanosoma cruzi, as well as the other trypanosomatids, must supply their quota of metal ions by importing them from their environment. Copper ions, and the heme group, constitute essential cofactors for aerobic organisms. This parasite must control the uptake of copper ions from the host, intracellular distribution, storage and insertion into target proteins. Considering that copper ions, in excess, are toxic to cells, T. cruzi must have strict control over its homeostasis. Furthermore, copper transporters and chaperones that have been identified in other organisms are not conserved in trypanosomatids. Therefore, the identification and characterization of these processes will allow the identification of novel proteins that fulfill essential functions, resulting in promising candidates to be validated as therapeutic targets for the design of new drugs for Chagas disease.


Selected Publications

  • The Trypanosoma cruzi protein TcHTE is critical for heme uptake. Plos Negledted Tropical Disease. 10(1): e0004359. Marcelo L. Merli, Lucas Pagura, Josefina Hernández, María Julia Barisón, Elizabeth M. F. Pral, Ariel M. Silber and Julia A. Cricco (2016) doi: 10.1371/journal.pntd0004359.
  • Heme A synthesis and CcO activity are essential for Trypanosoma cruzi infectivity and replication. Biochemichal Journal. 474, 2315–2332. Macelo L. Merli, Brenda A. Cirulli, Simón M. Menéndez-Bravo, and Julia A. Cricco* (2017) doi: 10.1042/BCJ20170084.
  • Biosynthesis of heme O in intraerythrocytic stages of Plasmodium falciparum and potential inhibitors of this pathway. Scientific Report. 9 (1): 19261. Simão-Gurge, Raquel Maria; Wunderlich, Gerhard; Cricco, Julia A.; Galindo Cubillos, Eliana F.; Doménech-Carbó, Antonio; Cebrián-Torrejón, Gerardo; Almeida, Fernando G.; Cirulli, Brenda A.; Katzin, Alejandro Miguel. (2019) doi: 10.1038/s41598-019-55506-y.
  • A new model for Trypanosoma cruzi heme homeostasis depends on modulation of TcHTE protein expression. Journal of Biological Chemistry 295, 13202–13212. Lucas Pagura, Evelyn Tevere, Marcelo L. Merli, Julia A. Cricco. (2020) doi: 10.1074/jbc.RA120.014574.

For a complete list, check my https://orcid.org/0000-0002-8993-3880, https://scholar.google.com/citations?user=sFnNN58AAAAJ&hl=en, https://www.researchgate.net/profile/Julia-Cricco