| First Author | Martínez A | Year | 2019 |
| Journal | Proc Natl Acad Sci U S A | Volume | 116 |
| Issue | 18 | Pages | 8879-8888 |
| PubMed ID | 30979807 | Mgi Jnum | J:355443 |
| Mgi Id | MGI:6297139 | Doi | 10.1073/pnas.1821487116 |
| Citation | Martinez A, et al. (2019) Cytosolic Fe-superoxide dismutase safeguards Trypanosoma cruzi from macrophage-derived superoxide radical. Proc Natl Acad Sci U S A 116(18):8879-8888 |
| abstractText | 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 ( approximately 28 and 8 microM, 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. |
