Cardiac and Digestive Forms of Chagas Disease: An Update on Pathogenesis, Genetics, and Therapeutic Targets

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.