Cytosolic Fe-superoxide dismutase safeguards Trypanosoma cruzi from macrophage-derived superoxide radical
| Autor: | Damián Estrada, Alejandra Martínez, Rafael Radi, Carolina Prolo, Lucía Piacenza, Natalia Rios, María Dolores Piñeyro, María Noel Alvarez, Carlos Robello |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Proceedings of the National Academy of Sciences. 116:8879-8888 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1821487116 |
| Popis: | Trypanosoma cruzi, the causative agent of Chagas disease (CD), contains exclusively Fe-dependent superoxide dismutases (Fe-SODs). During T. cruzi invasion to macrophages, superoxide radical (O2•−) is produced at the phagosomal compartment toward the internalized parasite via NOX-2 (gp91-phox) activation. In this work, T. cruzi cytosolic Fe-SODB overexpressers (pRIBOTEX–Fe-SODB) exhibited higher resistance to macrophage-dependent killing and enhanced intracellular proliferation compared with wild-type (WT) parasites. The higher infectivity of Fe-SODB overexpressers compared with WT parasites was lost in gp91-phox−/− macrophages, underscoring the role of O2•− in parasite killing. Herein, we studied the entrance of O2•− and its protonated form, perhydroxyl radical [(HO2•); pKa = 4.8], to T. cruzi at the phagosome compartment. At the acidic pH values of the phagosome lumen (pH 5.3 ± 0.1), high steady-state concentrations of O2•− and HO2• were estimated (∼28 and 8 µM, respectively). Phagosomal acidification was crucial for O2•− permeation, because inhibition of the macrophage H+-ATPase proton pump significantly decreased O2•− detection in the internalized parasite. Importantly, O2•− detection, aconitase inactivation, and peroxynitrite generation were lower in Fe-SODB than in WT parasites exposed to external fluxes of O2•− or during macrophage infections. Other mechanisms of O2•− entrance participate at neutral pH values, because the anion channel inhibitor 5-nitro-2-(3-phenylpropylamino) benzoic acid decreased O2•− detection. Finally, parasitemia and tissue parasite burden in mice were higher in Fe-SODB–overexpressing parasites, supporting the role of the cytosolic O2•−-catabolizing enzyme as a virulence factor for CD. |
| Databáze: | OpenAIRE |
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