Chagas Disease Cardiomyopathy: Immunopathology and Genetics

Abstract

Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and affects ca. 10 million people worldwide. About 30% of Chagas disease patients develop chronic Chagas disease cardiomyopathy (CCC), a particularly lethal inflammatory cardiomyopathy that occurs decades after the initial infection, while most patients remain asymptomatic. Mortality rate is higher than that of noninflammatory cardiomyopathy. CCC heart lesions present a Th1 T-cell-rich myocarditis, with cardiomyocyte hypertrophy and prominent fibrosis. Data suggest that the myocarditis plays a major pathogenetic role in disease progression. Major unmet goals include the thorough understanding of disease pathogenesis and therapeutic targets and identification of prognostic genetic factors. Chagas disease thus remains a neglected disease, with no vaccines or antiparasitic drugs proven efficient in chronically infected adults, when most patients are diagnosed. Both familial aggregation of CCC cases and the fact that only 30% of infected patients develop CCC suggest there might be a genetic component to disease susceptibility. Moreover, previous case-control studies have identified some genes associated to human susceptibility to CCC. In this paper, we will review the immunopathogenesis and genetics of Chagas disease, highlighting studies that shed light on the differential progression of Chagas disease patients to CCC.

Developments in the management of Chagas cardiomyopathy

“…[23,24] Activation of CD4 + and CD8 + T cells that synthesize Th1 cytokines generally correlates with myocardial damage, at least in experimental models, and may be modulated by IL-17 and T regulatory cells. [21,25,26] During acute infection, mononuclear cells produce high levels of IFN-γ,[27] TNF-α and IL-6. [28]…”

“…[31] Other inflammatory mediators including IL-18, TNF-α, CCL21 and CCL2 [32,33] may be involved in induction of transforming growth factor-β (TGF-β), the development of cardiac fibrosis and cardiac myocyte hypertrophy. [21]…”

Doença de Chagas – mais de 100 anos depois de sua cientificamente brilhante descoberta, há poucas razões para se comemorar?

“…Ainda nesse contexto, relatos recentes expõem a noção de que esse desequilíbrio imunológico possa ter sua base em polimorfismos genéticos do hospedeiro humano infectado pelo T. cruzi. (Cunha-Neto & Chevillard, 2014). De acordo com essa hipótese, aí poderia estar uma pista plausível para se desvendar o enigma de por que somente 30%-40% dos humanos infectados cronicamente desenvolvem a doença de Chagas propriamente dita (isto é, seriam geneticamente suscetíveis), enquanto os demais persistem por toda a vida com a forma indeterminada, isto é, sem manifestações clinicamente evidenciáveis (Rassi Jr. et al, 2017).…”

The potential influence of atherogenic dyslipidemia on the severity of chronic Chagas heart disease

“…1 It has been described recently that T. cruzi infection might be a risk factor for high blood pressure 2 and that it might induce cholesterol homeostasis disruption. 3 In this respect, Nagajyothi et al 4,5 have observed in an experimental murine model that T. cruzi infection promotes an important decrease of serum levels of low-density lipoprotein-cholesterol (LDL-c) and triglycerides (TG).…”