In Brazil, researchers at the University of São Paulo (USP) and their collaborators have identified a promising target for developing new Chagas disease treatments. In laboratory tests, the group succeeded in interrupting the infection cycle of the Trypanosoma cruzi parasite by reducing the production of one of its proteins.
Without adequate levels of this molecule, the pathogen lost its ability to differentiate into its infectious form within human heart cells, severely impairing its development. The discovery was detailed in an article published in August in the journal Communications Biology.
"We developed a version of the parasite deficient in the IP6K protein. It enters the cell and replicates, but with difficulty. Its differentiation into infectious forms is impaired, which leads to a reduction in blood forms with each new cycle of intracellular infection," explains Thaise Lara Teixeira , co-author of the study, which was conducted during her postdoctoral fellowship at the Institute of Chemistry (IQ) at USP.
Teixeira is currently a visiting professor in the Graduate Program in Applied Immunology and Parasitology at the Federal University of Uberlândia (PPGIPA-UFU).
According to the researchers, evidence that IP6K plays an important role in the life cycle of T. cruzi was the difficulty in producing laboratory strains of the parasite that did not express the protein.
"When both copies of the gene that codes for the IP6K protein were deleted through gene editing, the parasites simply didn't survive long enough for tests to be performed on cardiac cells. Therefore, the parasites used in the study still had one copy of the gene," says Bryan Etindi Abuchery , who participated in the research during his master's degree at the Botucatu Institute of Biosciences of São Paulo State University (IBB-UNESP), with support through a FAPESP scholarship .
Abuchery, a Kenyan national, is currently pursuing his Ph.D. at IQ-USP, also with a FAPESP scholarship . After earning his bachelor's degree in biology in Kenya, he interned at the U.S. Army Research Unit for Medical Sciences, where he monitored leishmaniasis in East Africa's endemic regions. During this time, a colleague sent him information about a FAPESP master's scholarship to work in Marcelo Santos da Silva 's laboratory. Silva, now a professor at IQ-USP, was a FAPESP Young Investigator at the time.
"I sent my resume and wasn't expecting a response. But he [Silva] liked it, called me in for an interview, and we talked at length about parasites. Then I took a test and passed," says the doctoral student, speaking good Portuguese.
While still pursuing his master's degree, Abuchery completed an internship at the University of Cincinnati in the United States, also with a FAPESP scholarship , where he contributed to the analyses described in the recently published study.
In the study, he and his colleagues investigated the IP6K protein precisely because its functions within an important but largely unexplored cellular signaling pathway are still poorly understood.
The assays showed that IP6K has a very low similarity – about 25% – to its human homolog. This is an important factor in ensuring that any future treatment targeting this protein would cause fewer side effects.
Life cycle
The life cycle of T. cruzi is relatively complex, which is one reason for its evolutionary success and resistance to treatments. The study's discovery of a way to interrupt this cycle is one factor that makes it promising.
"If with low levels of IP6K expression the parasite is already so impaired, it's possible to believe that, if a drug that can act specifically on that protein is developed, we'll have an effective treatment," Silva projects.
However, the researcher emphasizes the need for further studies to understand the role of IP6K in the life cycle of T. cruzi and to identify specific sites on the protein that could serve as targets for potential drugs.
T. cruzi has a life cycle involving two hosts: an invertebrate, typically a blood-feeding kissing bug, and a vertebrate, usually a mammal such as humans, dogs, rats, and wild animals.
Two of the parasite's four main forms occur while it is colonizing the kissing bug: the epimastigote and metacyclic forms. The latter typically infects humans through contact with the insect's feces or urine and a wound caused by the insect's bite.
Once in the human bloodstream, the parasite infects cells and begins the transition to the amastigote form within them. The amastigote form multiplies until it begins the transition to the blood-borne trypomastigote form. The tripomastigote leaves the cell and enters the bloodstream, where it can reinfect other cells or be ingested by another kissing bug. Once inside the insect, the parasite transforms back into the epimastigote form, restarting the cycle.
"Trypanosoma cruzi has a preference for cardiac cells. Over time, those cells are destroyed by the parasite and the local inflammatory response, without the immune system being able to completely repair the tissue. That leads to a loss of heart muscle function, to the point where the heart's ability to contract and pump blood to the rest of the body is reduced, causing the heart muscle to enlarge – a characteristic of the symptomatic chronic phase," explains Teixeira of UFU.
A neglected disease
According to the Ministry of Health, there were approximately 400 cases of Chagas disease in Brazil in 2025. The World Health Organization (WHO) estimates that the disease affects eight million people worldwide, most of whom are in Latin America.
After an acute phase with no symptoms or nonspecific symptoms – a period lasting between four and eight weeks – the disease progresses to the chronic stage. Years after infection, sometimes decades later, between 20% and 30% of patients develop heart problems that can lead to death, and about 10% experience digestive issues.
The two drugs available to treat the disease are still the same ones discovered in the 1970s, which are known to cause side effects that sometimes lead patients to discontinue treatment. They are also only effective in the early stages of the disease.
Due to limited treatment options, lack of interest from the pharmaceutical industry, and the fact that the disease primarily affects low-income populations, it is classified as one of the neglected tropical diseases.
In recent years, however, these diseases have received attention from the WHO and nonprofit initiatives aimed at discovering new drugs (read more at agencia.fapesp.br/30049 and agencia.fapesp.br/32265 ).
The recently published study opens up new avenues of research. As part of his doctoral work at IQ-USP, Abuchery is investigating whether IP6K plays a role in DNA repair, which could explain the protein's significance in the parasite's life cycle.
At UFU, Teixeira is coordinating studies to understand how the human immune system responds to IP6K-deficient T. cruzi. Silva, in turn, is developing a project to investigate how Leishmania – another parasite that causes the neglected disease leishmaniasis – responds to the absence of the IP6K protein.
About São Paulo Research Foundation (FAPESP)
The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at www.fapesp.br/en and visit FAPESP news agency at www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe.
