dinucleotide (NADH) and flavin adenine dinucleotide, which donate electrons to the electron transport chain to fuel oxidative phosphorylation (OXPHOS), the process by which 32 ATP molecules are generated in the mitochondria.In inflammatory settings, OXPHOS is inhibited by nitric oxide (NO) production in monocyte-derived inflammatory dendritic cells (moDCs) in an autocrine manner. In the absence of an active respiratory chain, sustained glycolytic metabolism is essential for moDC survival and function (9). Furthermore, NO production seems to be central in orchestrating HIF-1α responses by inducing its stabilization and transcriptional activation (10).Chagas disease, a complex pathological condition resulting from Trypanosoma cruzi infection, has become one of the most frequent causes of heart failure, cardio-embolic stroke, and sudden death in Latin America (11). The acute phase lasts 2-3 months and is characterized by detectable parasitemia and active parasite replication within target tissues. However, clinical symptoms are usually mild and nonspecific, and the vast majority of acute infections are never detected. During this phase, cell-mediated immunity controls parasite levels, but it is insufficient to completely clear the infection; most individuals remain infected for life. People who survive the acute phase enter a chronic asymptomatic phase (indeterminate stage), which is generally symptomless and may last from 10 to 30 years. Approximately 30% of patients in this period, also recognized as "silent," may develop heart abnormalities (12) that could give rise to the cardiac form of chronic infection. Although antiparasitic therapy is clearly recommended for acute Chagas disease, the treatment of patients in the chronic stage is controversial. This is largely due to a lack of large, randomized trials and incomplete understanding of pathological immune mechanisms developed during this stage. After decades of controversies, it is widely accepted nowadays that parasite persistence is a necessary and sufficient condition for the sustained inflammatory responses underlying the progression of cardiac lesions of chronic Chagas disease (13-18). Thus, one of the main challenges in understanding Chagas myocarditis immunopathology is to find out why, despite a robust immune response during the acute phase of the infection, the parasite is not completely eliminated, being able to sustain a pathological inflammatory environment.Cell-mediated immunity involves activation of phagocytes and of cytotoxic T lymphocytes (CTLs). In this sense, we have recently reported increased IL-1β plasma levels concomitant with enhanced frequency of NO-producing leukocytes and the surface nitration of CTLs associated with decreased functionality of this T cell compartment in the peripheral blood from patients with Chagas disease in the indeterminate phase (19). In this study, we went deeper by exploring how metabolism affects the monocyte compartment and T cell functionality during this human infectious disease. We have found that the nonc...
Infectious diseases are caused by the invasion of pathogenic microorganisms such as fungi, bacteria, viruses, and parasites. After infection, disease progression relies on the complex interplay between the host immune response and the microorganism evasion strategies. The host’s survival depends on its ability to mount an efficient protective anti-microbial response to accomplish pathogen clearance while simultaneously preventing tissue injury by keeping under control the excessive inflammatory process. The purinergic system has the dual function of regulating the immune response and triggering effector antimicrobial mechanisms. This review provides an overview of the current knowledge of the modulation of innate and adaptive immunity driven by the purinergic system during parasitic, bacterial and viral infections.
Chronic Chagas cardiomyopathy is the main infectious myocarditis worldwide. Almost 30% of Trypanosoma cruzi infected individuals develop slow and progressive myocarditis that leads to ventricular dilation and heart failure. Heart transplantation is an established, valuable therapeutic option for end-stage Chagas disease patients. Although the pathophysiology of Chagas disease has been addressed for decades by numerous groups, the cardiac immunologic mechanisms involved in the progression of clinical manifestation are still unknown. Growing evidence demonstrates that hypoxia-inducible factor (HIF)-1 plays indispensable roles in driving immune response by triggering the expression of CD73 purinergic ecto-enzyme. Purinergic system controls the duration and magnitude of purine signals directed to modulate immune cells through the conversion of extracellular ATP (microbicide/proinflammatory) to the immunoregulatory metabolite adenosine. In the present work, we described that infiltrating leukocytes within cardiac explants from patients with end-stage Chagas cardiomyopathy up-regulated HIF-1 and CD73 expression. Moreover, the number of HIF-1 + and CD73+ leukocytes positively correlated with the myocarditis severity and the local parasite load. Furthermore, we demonstrated a direct relationship between tissue parasite persistence and the influx of immune cells to the infected hearts, which ultimately determine the severity of the myocarditis. These findings provide evidence that CD73-dependent regulatory pathways are locally triggered in the myocardium of patients with end-stage Chagas disease.
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