Mitochondria are the energy center of the cell. They are found in the cell cytoplasm as dynamic networks where they adapt energy production based on the cell’s needs. They are also at the center of the proinflammatory response and have essential roles in the response against pathogenic infections. Mitochondria are a major site for production of Reactive Oxygen Species (ROS; or free radicals), which are essential to fight infection. However, excessive and uncontrolled production can become deleterious to the cell, leading to mitochondrial and tissue damage. Pathogens exploit the role of mitochondria during infection by affecting the oxidative phosphorylation mechanism (OXPHOS), mitochondrial network and disrupting the communication between the nucleus and the mitochondria. The role of mitochondria in these biological processes makes these organelle good targets for the development of therapeutic strategies. In this review, we presented a summary of the endosymbiotic origin of mitochondria and their involvement in the pathogen response, as well as the potential promising mitochondrial targets for the fight against infectious diseases and chronic inflammatory diseases.

Lista de Siglas/Abreviaturas 18 F-FDG – fluordesoxiglicose marcado com flúor-18 123 I-MIBG – meta-iodo-benzil-guanidina marcado com iodo-123 […] Diretriz da SBC sobre Diagnóstico e Tratamento de Pacientes com Cardiomiopatia da Doença de Chagas – 2023 Lista de Siglas/Abreviaturas 18 F-FDG – fluordesoxiglicose marcado com flúor-18 123 I-MIBG – meta-iodo-benzil-guanidina marcado com iodo-123 […] Diretriz da SBC sobre Diagnóstico e Tratamento de Pacientes com Cardiomiopatia da Doença de Chagas – 2023

Chronic Chagas disease cardiomyopathy (CCC), an especially aggressive inflammatory dilated cardiomyopathy caused by lifelong infection with the protozoan Trypanosoma cruzi, is a major cause of cardiomyopathy in Latin America. Although chronic myocarditis may play a major pathogenetic role, little is known about the molecular mechanisms responsible for its severity. The aim of this study is to study the genes and microRNAs expression in tissues and their connections in regards to the pathobiological processes. To do so, we integrated for the first time global microRNA and mRNA expression profiling from myocardial tissue of CCC patients employing pathways and network analyses. We observed an enrichment in biological processes and pathways associated with the immune response and metabolism. IFNγ, TNF and NFkB were the top upstream regulators. The intersections between differentially expressed microRNAs and differentially expressed target mRNAs showed an enrichment in biological processes such as Inflammation, inflammation, Th1/IFN-γ-inducible genes, fibrosis, hypertrophy, and mitochondrial/oxidative stress/antioxidant response. MicroRNAs also played a role in the regulation of gene expression involved in the key cardiomyopathy-related processes fibrosis, hypertrophy, myocarditis and arrhythmia. Significantly, a discrete number of differentially expressed microRNAs targeted a high number of differentially expressed mRNAs (>20) in multiple processes. Our results suggest that miRNAs orchestrate expression of multiple genes in the major pathophysiological processes in CCC heart tissue. This may have a bearing on pathogenesis, biomarkers and therapy.

Chagas disease (CD), caused by the protozoan parasite Trypanosoma cruzi, is a neglected disease affecting around 6 million people. About 30% of CD patients develop chronic Chagas disease cardiomyopathy (CCC), an inflammatory cardiomyopathy that occurs decades after the initial infection, while most infected patients (60%) remain asymptomatic in the so-called indeterminate form (IF). Death results from heart failure or arrhythmia in a subset of CCC patients. Myocardial fibrosis, inflammation, and mitochondrial dysfunction are involved in the arrhythmia substrate and triggering events. Survival in CCC is worse than in other cardiomyopathies, which may be linked to a Th1-T cell rich myocarditis with abundant interferon (IFN)-γ and tumor necrosis factor (TNF)-α, selectively lower levels of mitochondrial energy metabolism enzymes in the heart, and reduced levels of high-energy phosphate, indicating poor adenosine triphosphate (ATP) production. IFN-γ and TNF-α signaling, which are constitutively upregulated in CD patients, negatively affect mitochondrial function in cardiomyocytes, recapitulating findings in CCC heart tissue. Genetic studies such as whole-exome sequencing (WES) in nuclear families with multiple CCC/IF cases has disclosed rare heterozygous pathogenic variants in mitochondrial and inflammatory genes segregating in CCC cases. In this minireview, we summarized studies showing how IFN-γ and TNF-α affect cell energy generation, mitochondrial health, and redox homeostasis in cardiomyocytes, in addition to human CD and mitochondria. We hypothesize that cytokine-induced mitochondrial dysfunction in genetically predisposed patients may be the underlying cause of CCC severity and we believe this mechanism may have a bearing on other inflammatory cardiomyopathies.

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi ( T. cruzi ), is a neglected disease affecting around 6 million people, with no effective antiparasitic drugs or vaccines. About 40% of Chagas disease patients develop symptomatic forms in the chronic phase of infection, chronic Chagas cardiomyopathy (CCC) or digestive forms like megaoesophagus and megacolon, while most infected patients (60%) remain asymptomatic (ASY) in the so‐called indeterminate form (IF). CCC is an inflammatory cardiomyopathy that occurs decades after the initial infection. Death results from heart failure or arrhythmia in a subset of CCC patients. Myocardial fibrosis, inflammation, and mitochondrial dysfunction are involved in heart failure and arrhythmia. Survival in CCC is worse than in other cardiomyopathies. Distinct from other cardiomyopathies, CCC displays a helper T‐cell type 1 (Th1‐T) cell–rich myocarditis with abundant interferon‐gamma (IFN‐ γ ) and tumor necrosis factor‐alpha (TNF‐ α ) and selectively lower levels of mitochondrial energy metabolism enzymes and high‐energy phosphates in the heart. A CD8+ T cell–rich inflammatory infiltrate has also been found in the Chagasic megaesophagus, which is associated with denervation of myoenteric plexi. IFN‐ γ and TNF‐ α signaling, which are constitutively upregulated in Chagas disease patients, negatively affect mitochondrial function and adenosine 5′‐triphosphate (ATP) production–cytokine‐induced mitochondrial dysfunction. In addition, the differential susceptibility to developing CCC has prompted many studies over the past 25 years on the association of genetic polymorphisms with disease outcomes. A comprehensive understanding of Chagas disease pathogenesis is crucial for identifying potential therapeutic targets. Genetic studies may offer valuable insights into factors with prognostic significance. In this review, we present an updated perspective on the pathogenesis and genetic factors associated with Chagas disease, emphasizing key studies that elucidate the differential progression of patients to CCC and other symptomatic forms. Furthermore, we explore the interplay between genetic susceptibility, inflammatory cytokines, mitochondrial dysfunction and discuss emerging therapeutic targets.

Recurrence of COVID-19 in recovered patients has been increasingly reported. However, the immune mechanisms behind the recurrence have not been thoroughly investigated. The presence of neutralizing antibodies (nAbs) in recurrence/reinfection cases suggests that other types of immune response are involved in protection against recurrence. Here, we investigated the innate type I/III interferon (IFN) response, binding and nAb assays and T-cell responses to severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) with IFN gamma (IFN γ ) enzyme-linked spot assay (ELISPOT) in three pairs of young adult monozygotic (MZ) twins with previous confirmed COVID-19, one of them presenting a severe recurrence four months after the initial infection. Twin studies have been of paramount importance to comprehend the immunogenetics of infectious diseases. Each MZ twin pair was previously exposed to SARS-CoV-2, as seen by clinical reports. The six individuals presented similar overall recovered immune responses except for the recurrence case, who presented a drastically reduced number of recognized SARS-CoV-2 T-cell epitopes on ELISPOT as compared to her twin sister and the other twin pairs. Our results suggest that the lack of a broad T-cell response to initial infection may have led to recurrence, emphasizing that an effective SARS-CoV-2-specific T-cell immune response is key for complete viral control and avoidance of clinical recurrence of COVID-19.