Abstract
Clinical symptoms of chronic Chagas disease occur in around 30% of the individuals infected with Trypanosoma cruzi and are characterized by heart inflammation and dysfunction. The pathogenesis of chronic chagasic cardiomyopathy (CCC) is not completely understood yet, partially because disease evolution depends on complex host-parasite interactions. Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory cytokine that promotes numerous pathophysiological processes. In the current study, we investigated the link between MIF and CCC progression.Immunohistochemical analysis demonstrated MIF overexpression in the hearts from chronically T. cruzi-infected mice, particularly those showing intense inflammatory infiltration. We also found that MIF exogenously added to parasite-infected murine macrophage cultures is capable of enhancing the production of TNF-α and reactive oxygen species, both with pathogenic roles in CCC. Thus, the integrated action of MIF and other cytokines and chemokines may account for leukocyte influx to the infected myocardium, accompanied by enhanced local production of multiple inflammatory mediators. We further examined by ELISA the level of MIF in the sera from chronic indeterminate and cardiomyopathic chagasic patients, and healthy subjects. CCC patients displayed significantly higher MIF concentrations than those recorded in asymptomatic T. cruzi-infected and uninfected individuals. Interestingly, increased MIF levels were associated with severe progressive Chagas heart disease, in correlation with elevated serum concentration of high sensitivity C-reactive protein and also with several echocardiographic indicators of left ventricular dysfunction, one of the hallmarks of CCC. Our present findings represent the first evidence that enhanced MIF production is associated with progressive cardiac impairment in chronic human infection with T. cruzi, strengthening the relationship between inflammatory response and parasite-driven pathology. These observations contribute to unravel the elements involved in the pathogenesis of CCC and may also be helpful for the design of novel therapies aimed to control long-term morbidity in chagasic patients.
Highlights
Chagas disease, caused by infection with the hemoflagellate protozoan Trypanosoma cruzi, is endemic in South and Central America, where an estimated 10 million patients are infected and another 100–120 million people are at risk of contracting the illness [1]
T. cruzi-driven induction of migration inhibitory factor (MIF) in the hearts from chronically infected mice was investigated by immunohistochemistry
As MIF has been originally found to inhibit the random migration of monocytes/macrophages [32], we asked whether the local expression of this proinflammatory cytokine could lead to mononuclear cell recruitment to and accumulation in cardiac tissues from chagasic cardiomyopathy (CCC) mice
Summary
Chagas disease, caused by infection with the hemoflagellate protozoan Trypanosoma cruzi, is endemic in South and Central America, where an estimated 10 million patients are infected and another 100–120 million people are at risk of contracting the illness [1]. The pathogenesis of chronic chagasic cardiomyopathy (CCC) is not completely understood, partially because disease progression depends on complex host-parasite interactions. The main cardiac pathologic finding in Chagas disease patients is chronic progressive myocarditis [4,5,6], in which an important mononuclear infiltrate is accompanied by interstitial fibrosis and cardiomyocyte hypertrophy leading to dilated cardiomyopathy and ventricular systolic disorder that result in poor prognoses and high premature mortality rates [7]. It is widely accepted that the inflammatory infiltrate is the ultimate effector of myocardial damage and increased local expression of proinflammatory cytokines, chemokines, vascular mediators, HLA class I and II antigens, and adhesion molecules has been shown to contribute to T. cruzi-mediated heart dysfunction [8]
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