Chagas disease, which is caused by a protozoan parasite Trypanosoma cruzi It affects about 8 million people worldwide. More than a third of them have severe heart or digestive problems with an increased risk of death. The process that leads to this clinical condition is not fully understood.
Article published in the journal Biomedicine He describes a study led by Brazilian researchers showing that mutations occurred in the mitochondrial genes of patients with Chagas disease, a disorder in which the esophagus expands and loses its motion. 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, which leads to mitochondrial dysfunction in neurons. Degeneration of nerve cells in the lining of the esophagus contributes to the development of the disorder.
"After years of research, we have been able to achieve a better understanding of mitochondrial dysfunction caused by interferon-gamma. The importance of this discovery lies in the opportunity it provides to search for specific drugs that can mitigate the change.”
Edecio Cunha-Neto, author of the last article
Immunologist and researcher at the Institute of Heart (INCOR) run by the Faculty of Medicine of the University of São Paulo (FM-USP), where he is a professor in the Department of Clinical Medicine, Kunha Neto is one of the corresponding authors of the article. The other is Christophe Chevellard, a researcher at Aix-Marseille University in France. The study was supported by FAPESP.
Kunya Neto has studied Chagas disease for more than 30 years and is particularly interested in cases of cardiomyopathy caused by the disease. He previously explained that these patients present with an inflammatory change, measured in terms of blood levels of interferon-gamma. In this study, researchers analyzed material from the hearts of Chagas patients who underwent heart transplants, and observed a disruption in the organ’s energy metabolism, with decreased levels of a large number of proteins and enzymes involved in the production of ATP (adenosine triphosphate), the main source of cellular energy and involved in Making RNA. These results confirmed previous in vivo observations of reduced energy metabolism in the hearts of Chagas patients.
In one previous study, for example, high levels of interferon-gamma in patients with cardiomyopathy due to Chagas disease were found to decrease cellular energy metabolism, leading to mitochondrial dysfunction in heart tissue.
Mitochondria are organelles that provide cells with energy. They have their own genome – mitochondrial DNA or mtDNA – with 16,569 nucleotides prone to mutations. About 1,500 mitochondrial genes are encoded in the cell nucleus. Certain mutations can lead to the development of mitochondrial disease.
“We treated heart muscle cells with interferon-gamma and observed a decrease in ATP production, which led us to hypothesize that interferon-gamma was also involved in other symptoms of the disease, reducing mitochondrial function. We decided to study esophageal cases,” Cunha-Neto said.
About 10% of all Chagas patients experience gastrointestinal changes, and 30% develop heart problems, according to estimates. About 60% of these die within two years, compared to 30% for patients with other types of cardiomyopathy. In October, the Brazilian Society of Cardiology (SBC) released new guidelines on Chagas’ disease cardiomyopathy, including new treatment recommendations.
The World Health Organization (WHO) classifies Chagas disease as a neglected tropical disease (NTD). The disease is mainly spread by infected triatomines or kissing bugs that defecate after biting the victim. T. Cruze Parasites in feces can enter the body through mucous membranes or cracks in the skin.
Other vectors are becoming increasingly important in many countries including Brazil, such as ingestion of food contaminated by infected insects, transmission of the parasite from mother to fetus during pregnancy, and blood transfusions and organ transplants. The earlier the diagnosis is made, the sooner the patient can be treated with the better chances of recovery.
Genetic analysis
By sequencing exomes (protein-coding regions of the genome), researchers previously observed an association between rare mitochondrial genetic variants and chronic Chagas cardiomyopathy in families with multiple cases of Chagas disease.
In the recently published study, the group sequenced the whole exomes of 13 patients with massive Chagas disease. About 40% have the same mitochondrial variant (MRPS18B P230A), which is present in 18% of patients with chronic Chagas cardiomyopathy but only in 2% of the total Brazilian population.
The patient’s lymphoblastic cell lines with and without the mutation were analyzed to evaluate 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 in cells taken from patients without the mutation.
The group recently got a new line of research approved to analyze the cases of families with mitochondrial mutations. The idea is to study the effects of model processing with inhibitors of interferon-gamma signaling and substances that protect mitochondria. Substances that may be used include metformin, a drug used to control type 2 diabetes, and resveratrol, a plant-derived compound that has antioxidant effects. Both have been shown to attenuate mitochondrial dysfunction caused by interferon-gamma in cardiac muscle cells.
“We plan to screen 1,700 drugs that have already been given to patients and are known to be safe to see if we can find other drugs that have a mitigating effect on the action of interferon-gamma on heart muscle cells,” Kunya Netto said.
source:
São Paulo Research Foundation (FAPESP)
Journal reference:
Silva, KDA, et al. (2022) Chagas esophageal patients carrying the MRPS18B p260A variant display oxidative stress and mitochondrial dysfunction in response to an IFN-γ stimulus. Biomedicine. doi.org/10.3390/biomedicines10092215.
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