Caused by the protozoan parasite Trypanosoma cruzi, Chagas disease affects approximately 8 million people worldwide. More than a third will develop severe heart or digestive problems, putting them at increased risk of death. The processes that lead to this clinical state are not fully understood.
Articles published in magazines biomedical It describes a study led by Brazilian researchers showing mutations in mitochondrial genes in patients with megaesophageal Chagas disease, a dilated, nonmotile esophagus. This discovery may pave the way for the development of new treatments.
This study suggests that increased production of the inflammatory mediator cytokine interferon-gamma in people with these mutations results in oxidative stress, leading to mitochondrial dysfunction in neurons. Neuronal degeneration in the lining of the esophagus contributes to the development of this disease.
“Years of research have led to a better understanding of the mitochondrial dysfunction induced by interferon gamma. is to provide a , the article’s last author told Agência FAPESP.
Cunha-Neto, an immunologist, investigator at the Heart Institute (INCOR) run by the University of São Paulo School of Medicine (FM-USP) and professor at the School of Clinical Medicine, wrote the paper. Another is Christophe Cheubillard, a researcher at the University of Aix-Marseille in France.
Cunha-Neto has studied Chagas disease for over 30 years and has a particular interest in cases of cardiomyopathy caused by this disease. These patients had previously been shown to have inflammatory changes as measured by blood levels of interferon gamma, he explained.
In this study, researchers analyzed material taken from the hearts of Chagas patients who underwent heart transplants and found that the organ’s energy levels were accompanied by decreased levels of numerous proteins and enzymes related to the production of ATP (adenosine triphosphate). Observed metabolic disturbances. Main source of cellular energy and involved in making RNA. These results corroborated previous in vivo observations of decreased energy metabolism in the heart of Chagas patients.
in 2021 The forefront of immunology For example, studies have found that high levels of interferon-gamma in patients with Chagas cardiomyopathy reduce cellular energy metabolism and lead 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 nucleotide mutations. Approximately 1,500 mitochondrial genes are encoded in the cell nucleus. Some mutations can lead to the development of mitochondrial diseases.
“When we treated cardiomyocytes with interferon-gamma, we observed a decrease in ATP production. We decided to study cases of megaesophagus,” said Cunha-Neto.
It is estimated that approximately 10% of all Chagas patients have gastrointestinal changes and 30% have heart problems. About 60% of the latter he dies within 2 years, while in patients with other types of cardiomyopathy he is 30%. In October, the Brazilian Society of Cardiology (SBC) published new guidelines for Chagas cardiomyopathy. It contains new treatment recommendations.
The World Health Organization (WHO) has classified Chagas as a neglected tropical disease (NTD). It is mainly spread by infected triatomine or kissing bugs, which are excreted after biting the victim.
In some countries, including Brazil, other vectors such as ingestion of food contaminated with infected worms, transmission of parasites from pregnant mothers to fetuses, blood transfusions, and organ transplants are becoming increasingly important. . The sooner the diagnosis is made, the sooner patients can receive treatment and the more likely they are to be cured.
genetic analysis
By sequencing the exome (the protein-coding region of the genome), researchers had previously observed an association between rare mitochondrial gene variants and chronic Chagas cardiomyopathy in families with multiple Chagas cases. rice field.
In a recently published study, the group sequenced the entire exome of 13 patients with Chagas esophagus. About 40% had the same mitochondrial variant (MRPS18B P230A). It is found in 18% of patients with chronic Chagas cardiomyopathy, but only in his 2% of the total Brazilian population.
To assess the effects of interferon-gamma on mitochondrial function, we analyzed lymphoblastoid cell lines from patients with and without mutations. One patient was homozygous for the mitochondrial mutation and showed lower ATP production in the presence of interferon-γ than cells from patients without the mutation.
The group recently had a new line of research approved to analyze cases in families with mitochondrial mutations. Substances that could be used include metformin, a drug used to control type 2 diabetes, and resveratrol, a plant-derived compound with antioxidant properties. both have been shown to reduce Mitochondrial dysfunction Induced by interferon-gamma in cardiomyocytes.
“To see if we can find other drugs that have been administered to patients and have the effect of mitigating the effects of interferon gamma on heart muscle cells, they have been administered to patients and found to be safe. We plan to screen 1,700 drugs,” said Cunha-Neto.
For more information:
Karla Deysiree Alcântara Silva et al., Chagas Disease Megaesophagus Patients Carrying Variant MRPS18B P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus, biomedical (2022). DOI: 10.3390/Biomedicine 10092215
Priscila Camillo Teixeira et al, Impairment of multiple mitochondrial energy metabolism pathways in the heart of patients with Chagas disease cardiomyopathy, The forefront of immunology (2021). DOI: 10.3389/fimmu.2021.755782