Cardiomyocyte diffusible redox mediators control Trypanosoma cruzi infection: role of parasite mitochondrial iron superoxide dismutase

Chagas disease (CD), caused by the protozoa Trypanosoma cruzi , is a chronic illness in which parasites persist in the host-infected tissues for years. T. cruzi invasion in cardiomyocytes elicits the production of pro-inflammatory mediators (TNF-α, IL-1β, IFNγ; nitric oxide ( • NO)) leading to mitochondrial dysfunction with increase superoxide radical (O 2 •- ), hydrogen peroxide (H 2 O 2 ) and peroxynitrite generation. We hypothesize that these redox-mediators may control parasite proliferation through the induction of intracellular amastigote programmed cell death (PCD). In this work we show that T. cruzi (CL-Brener strain) infection in primary cardiomyocytes produced an early (24 hs post-infection) mitochondrial dysfunction with H 2 O 2 generation and the establishment of an oxidative stress evidenced by FoxO3 activation and target mitochondrial gene induction (MnSOD and peroxiredoxin 3). TNF-α/IL-1β stimulated cardiomyocytes were able to control intracellular amastigote proliferation compared to un-stimulated cardiomyocytes. In this condition (presence of H 2 O 2 or • NO), an enhanced number of intracellular apoptotic amastigotes were detected. The ability of H 2 O 2 to induce T. cruzi PCD was further confirmed in the epimastigote stage of the parasite. H 2 O 2 -treatment induced parasite mitochondrial dysfunction together with intra-mitochondrial O 2 •- generation. Importantly, parasites genetically-engineered to overexpress mitochondrial Fe-superoxide dismutase (Fe-SODA) were more infective to TNF-α/IL-1β stimulated cardiomyocytes with less apoptotic amastigotes; this result underscores the role of this enzyme in parasite survival. Our results indicate that cardiomyocyte-derived diffusible mediators are able to control intracellular amastigote proliferation by triggering T. cruzi PCD and that parasite Fe-SODA tilts the process towards survival as part of an antioxidant-based immune evasion mechanism.