Frade Amanda Farage, Guérin Hélléa, Nunes Joao Paulo Silva, Silva Luiz Felipe Souza E, Roda Vinicius Moraes de Paiva, Madeira Rafael Pedro, Brochet Pauline, Andrieux Pauline, Kalil Jorge, Chevillard Christophe, Cunha-Neto Edecio
Laboratory of Immunology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo 05403-900, Brazil.
French National Institute for Health and Medical Research (INSERM), UMR U1090, TAGC Theories and Approaches of Genomic Complexity, MarMaRa Institute, Aix Marseille University, Marseille 13288, France.
Mediators Inflamm. 2025 Apr 21;2025:8862004. doi: 10.1155/mi/8862004. eCollection 2025.
Chagas disease, caused by the protozoan parasite (), 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-) and tumor necrosis factor-alpha (TNF-) 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- and TNF- 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.
恰加斯病由原生动物寄生虫（）引起，是一种被忽视的疾病，影响着约600万人，目前尚无有效的抗寄生虫药物或疫苗。约40%的恰加斯病患者在感染的慢性期会出现症状性形式，如慢性恰加斯心肌病（CCC）或诸如巨食管和巨结肠等消化形式，而大多数感染患者（60%）在所谓的不确定形式（IF）中仍无症状（ASY）。CCC是一种炎症性心肌病，在初次感染数十年后发生。一部分CCC患者会因心力衰竭或心律失常而死亡。心肌纤维化、炎症和线粒体功能障碍与心力衰竭和心律失常有关。CCC患者的生存率低于其他心肌病患者。与其他心肌病不同，CCC表现为富含辅助性T细胞1型（Th1-T）细胞的心肌炎，伴有大量干扰素-γ（IFN-）和肿瘤坏死因子-α（TNF-），且心脏中线粒体能量代谢酶和高能磷酸盐水平选择性降低。在恰加斯病巨食管中也发现了富含CD8+T细胞的炎性浸润，这与肌间神经丛的去神经支配有关。在恰加斯病患者中持续上调的IFN-和TNF-信号传导对线粒体功能和腺苷5'-三磷酸（ATP）产生有负面影响——细胞因子诱导的线粒体功能障碍。此外，对发生CCC的不同易感性促使在过去25年中进行了许多关于基因多态性与疾病结局关联的研究。全面了解恰加斯病的发病机制对于确定潜在治疗靶点至关重要。基因研究可能为具有预后意义的因素提供有价值的见解。在本综述中，我们呈现了关于恰加斯病发病机制和遗传因素的最新观点，强调了阐明患者向CCC和其他症状性形式不同进展的关键研究。此外，我们探讨了遗传易感性、炎性细胞因子和线粒体功能障碍之间的相互作用，并讨论了新出现的治疗靶点。
