Avaliação de parâmetros imunológicos associados à patogênese da cardiopatia chagásica crônica: estudo comparativo com cardiopatias etiologicamente distintas e com a Doença de Chagas assintomática

Abstract

Chagas disease, caused by the intracellular protozoan Trypanosoma cruzi, remains a significant public and social health challenge in Central and South American countries, displaying high morbidity and mortality rates despite advancements in control and prevention efforts. In the chronic phase of the disease, approximately 70% of infected individuals remain asymptomatic throughout their lives, classified as having the indeterminate clinical form (IND). However, 30% progress to Chronic Chagas Cardiomyopathy (CCC), one of the most lethal cardiac diseases in endemic regions, causing over 10.000 deaths annually. CCC exhibits an unfavorable clinical prognosis compared to other cardiopathies, possibly due to its predominantly inflammatory nature. Despite the crucial role of infectious etiology in CCC severity, gaps persist in understanding specific or shared immunological factors with other cardiopathies. In this context, we propose to assess the immune profile of CCC patients compared to etiologically distinct heart conditions and the asymptomatic form of Chagas disease. For comparative purposes, we selected chronic Rheumatic Heart Disease (RHD), prevalent in low-income countries, and idiopathic dilated cardiomyopathy (IDC), a leading cause of heart transplantation in Brazil. Evaluation of the systemic immune profile of CCC patients compared to RHD revealed more intense immune activation in Chagas disease-related cardiopathy, evidenced by elevated plasma levels of cytokines, chemokines, and growth factors. The study of the phenotypic and functional profiles of T lymphocyte subpopulations, combined with in silico analysis of cardiac tissue, indicated a strong association between inflammatory and cytotoxic CD8+ T cells and CCC. In contrast, CD4+ T cells were associated with IDC. Furthermore, based on clinical evidence of mitral regurgitation in CCC and IDC patients, we assessed the protein profile expressed in mitral valves using liquid chromatography coupled with mass spectrometry to identify potential targets associated with valvular immunopathology in these diseases. Our data showed enrichment of proteins involved in humoral and cellular immune response pathways in CCC, while proteins associated with mitochondrial metabolic processes exhibited reduction. Importantly, proteins were shared between CCC and IDC, including increased expression of STAT1, a transcription factor involved in the IFN-γ signaling pathway, and decreased expression of proteins linked to innate immune signaling pathways. We also evaluated the immunoregulatory, chemotactic, and cytotoxic profiles of circulating DN TCR αβ+ and  T cells in CCC patients compared to the IND. Interestingly, our data revealed that DN T cells from CCC patients are more inflammatory and cytotoxic than those from the asymptomatic clinical form. Importantly, blocking the activation of DN αβ+ T cells proved to be a promising strategy for reducing their inflammatory profile. Our findings highlight immunological characteristics potentially associated with cardiac pathology in CCC, either in terms of their uniqueness or similarities with other heart conditions and asymptomatic Chagas disease. This study may guide the design of prevention and treatment strategies for the evaluated heart conditions and provide insight into avenues for preventing and controlling Chagas disease progression.