Discovery paves way for development of new therapies for Chagas disease

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects some 8 million people worldwide. More than a third develop serious heart or digestive problems with an increased risk of death. The process that leads to this clinical condition is not completely understood.

An article published in the journal Biomedicines describes a study by Brazilian researchers showing that mutations occurred in the mitochondrial genes of patients with Chagas disease megaesophagus, a disorder in which the esophagus dilates and loses motility. This discovery could pave the way for the development of new treatments.

The study suggests that increased production of the cytokine interferon-gamma, an inflammatory mediator, in people with these mutations causes oxidative stress, leading to mitochondrial dysfunction in neurons. The degeneration of neurons in the lining of the esophagus contributes to the development of the disease.

After years of research, we were able to come to a better understanding of mitochondrial dysfunction induced by interferon-gamma. The importance of this discovery is the chance it offers to search for specific drugs that can alleviate the impairment.”

Edecio Cunha-Neto, last author of the article

Immunologist and researcher at the Institute of Cardiology (INCOR) of the Faculty of Medicine of the University of São Paulo (FM-USP), where he is a professor in the Department of Clinical Medicine, Cunha-Neto is one of the corresponding authors of the article. The other is Christophe Chevillard, a researcher at the University of Aix-Marseille in France. The study was funded by FAPESP.

Cunha-Neto has studied Chagas disease for over 30 years and has a particular interest in cases of cardiomyopathy caused by the disease. These patients have previously been shown to have inflammatory impairment, measured in terms of blood levels of interferon gamma, he explained. In the study, researchers analyzed material from the hearts of Chagas patients undergoing heart transplantation and observed disruption of the organ’s energy metabolism, with reduced levels of a large number of proteins and enzymes linked to the production of ATP (adenosine triphosphate), the main source of cellular energy and involved in the production of RNA. These results corroborated previous in vivo observations of reduced energy metabolism in the hearts of Chagas patients.

In a previous study, for example, high levels of interferon gamma in patients with Chagas cardiomyopathy were found to lower cellular energy metabolism, leading to mitochondrial dysfunction in heart tissue.

Mitochondria are organelles that provide energy to cells. They have their own genome – mitochondrial DNA or mtDNA – with 16,569 nucleotides subject to mutations. About 1,500 mitochondrial genes are encoded in cell nuclei. Certain mutations can lead to the development of mitochondrial disease.

“We treated cardiomyocytes with interferon-gamma and observed a decrease in ATP production, leading us to speculate that interferon-gamma was also involved in other disease symptoms, reducing mitochondrial function. We decided to study cases of mega-esophagus,” said Cunha- dit Néto.

About 10% of all Chagas patients have digestive disorders and 30% have heart problems, according to estimates. About 60% of these die within two years, compared to 30% for subjects with other types of cardiomyopathy. In October, the Brazilian Society of Cardiology (SBC) released new guidelines on Chagas cardiomyopathy, including new treatment recommendations.

The World Health Organization (WHO) classifies Chagas as a neglected tropical disease (NTD). It is mainly spread by infected triatomine bugs or bedbugs that defecate after biting the victim. T.cruzi parasites in faeces can enter the body through mucous membranes or skin lesions.

Other vectors are increasingly important in several countries including Brazil, such as the consumption of food contaminated by infected insects, transmission of the parasite from mother to fetus during pregnancy, blood transfusions and organ transplants. organs. The earlier the diagnosis, the sooner the patient can be treated with a better chance of recovery.

Genetic analysis

By sequencing the exome (the protein-coding regions of the genome), researchers had previously observed an association between rare mitochondrial genetic variants and chronic Chagas cardiomyopathy in families with multiple cases of Chagas.

In the recently published study, the group sequenced the whole exome of 13 patients with Chagas megaesophagus. About 40% had the same mitochondrial variant (MRPS18B P230A), which is found in 18% of patients with chronic Chagas cardiomyopathy, but only in 2% of the total Brazilian population.

Lymphoblastoid cell lines from patients with and without the mutation were analyzed to assess the effect of interferon gamma on mitochondrial function. One patient was homozygous for the mitochondrial mutation and showed lower ATP production in the presence of interferon gamma than cells from patients without the mutation.

The group recently got approval for a new line of research to analyze cases of families with mitochondrial mutations. The idea is to study the effects of treating models with interferon gamma signaling inhibitors and substances that protect mitochondria. Substances that could be used include metformin, a drug used to control type 2 diabetes, and resveratrol, a plant-derived compound with antioxidant effects. Both have been shown to attenuate interferon gamma-induced mitochondrial dysfunction in cardiomyocytes.

“We plan to screen 1,700 drugs already given to patients and known to be safe to see if we can find any others that have this attenuating effect on the action of interferon gamma on cardiomyocytes,” Cunha- said. neto.