Intraphagosomal Peroxynitrite As a Macrophage-derived Cytotoxin Against Internalized Trypanosoma Cruzi: Consequences for Oxidative Killing and Role of Microbial Peroxiredoxins in Infectivity

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2010 Nov 25

PMID 21098483

Citations 97

Authors

Maria Noel Alvarez

Gonzalo Peluffo

Lucia Piacenza

Rafael Radi

Affiliations

Soon will be listed here.

Abstract

Macrophage-derived radicals generated by the NADPH oxidase complex and inducible nitric-oxide synthase (iNOS) participate in cytotoxic mechanisms against microorganisms. Nitric oxide ((•)NO) plays a central role in the control of acute infection by Trypanosoma cruzi, the causative agent of Chagas disease, and we have proposed that much of its action relies on macrophage-derived peroxynitrite (ONOO(-) + ONOOH) formation, a strong oxidant arising from the reaction of (•)NO with superoxide radical (O(2)(-)). Herein, we have shown that internalization of T. cruzi trypomastigotes by macrophages triggers the assembly of the NADPH oxidase complex to yield O(2)(-) during a 60-90-min period. This does not interfere with IFN-γ-dependent iNOS induction and a sustained (•)NO production (∼24 h). The major mechanism for infection control via reactive species formation occurred when (•)NO and O(2)() were produced simultaneously, generating intraphagosomal peroxynitrite levels compatible with microbial killing. Moreover, biochemical and ultrastructural analysis confirmed cellular oxidative damage and morphological disruption in internalized parasites. Overexpression of cytosolic tryparedoxin peroxidase in T. cruzi neutralized macrophage-derived peroxynitrite-dependent cytotoxicity to parasites and favored the infection in an animal model. Collectively, the data provide, for the first time, direct support for the action of peroxynitrite as an intraphagosomal cytotoxin against pathogens and the premise that microbial peroxiredoxins facilitate infectivity via decomposition of macrophage-derived peroxynitrite.

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References

Cassina P, Cassina A, Pehar M, Castellanos R, Gandelman M, de Leon A . Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration: prevention by mitochondrial-targeted antioxidants. J Neurosci. 2008; 28(16):4115-22. PMC: 3844766. DOI: 10.1523/JNEUROSCI.5308-07.2008. View

Bergeron M, Olivier M . Trypanosoma cruzi-mediated IFN-gamma-inducible nitric oxide output in macrophages is regulated by iNOS mRNA stability. J Immunol. 2006; 177(9):6271-80. DOI: 10.4049/jimmunol.177.9.6271. View

Gookin J, Allen J, Chiang S, Duckett L, Armstrong M . Local peroxynitrite formation contributes to early control of Cryptosporidium parvum infection. Infect Immun. 2005; 73(7):3929-36. PMC: 1168623. DOI: 10.1128/IAI.73.7.3929-3936.2005. View

Piacenza L, Peluffo G, Radi R . L-arginine-dependent suppression of apoptosis in Trypanosoma cruzi: contribution of the nitric oxide and polyamine pathways. Proc Natl Acad Sci U S A. 2001; 98(13):7301-6. PMC: 34663. DOI: 10.1073/pnas.121520398. View

Mohapatra N, Soni S, Rajaram M, Dang P, Reilly T, El-Benna J . Francisella acid phosphatases inactivate the NADPH oxidase in human phagocytes. J Immunol. 2010; 184(9):5141-50. PMC: 2952287. DOI: 10.4049/jimmunol.0903413. View

Szabo C, Ischiropoulos H, Radi R . Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov. 2007; 6(8):662-80. DOI: 10.1038/nrd2222. View

Brito C, Naviliat M, Tiscornia A, Vuillier F, Gualco G, Dighiero G . Peroxynitrite inhibits T lymphocyte activation and proliferation by promoting impairment of tyrosine phosphorylation and peroxynitrite-driven apoptotic death. J Immunol. 1999; 162(6):3356-66. View

Alvarez M, Trujillo M, Radi R . Peroxynitrite formation from biochemical and cellular fluxes of nitric oxide and superoxide. Methods Enzymol. 2002; 359:353-66. DOI: 10.1016/s0076-6879(02)59198-9. View

Stempin C, Giordanengo L, Gea S, Cerban F . Alternative activation and increase of Trypanosoma cruzi survival in murine macrophages stimulated by cruzipain, a parasite antigen. J Leukoc Biol. 2002; 72(4):727-34. View

10.

Xie Q, Whisnant R, Nathan C . Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon gamma and bacterial lipopolysaccharide. J Exp Med. 1993; 177(6):1779-84. PMC: 2191051. DOI: 10.1084/jem.177.6.1779. View

11.

Reed S, Nathan C, Pihl D, Rodricks P, Shanebeck K, Conlon P . Recombinant granulocyte/macrophage colony-stimulating factor activates macrophages to inhibit Trypanosoma cruzi and release hydrogen peroxide. Comparison with interferon gamma. J Exp Med. 1987; 166(6):1734-46. PMC: 2188783. DOI: 10.1084/jem.166.6.1734. View

12.

MacMicking J, Xie Q, Nathan C . Nitric oxide and macrophage function. Annu Rev Immunol. 1997; 15:323-50. DOI: 10.1146/annurev.immunol.15.1.323. View

13.

Barr S, Gedamu L . Role of peroxidoxins in Leishmania chagasi survival. Evidence of an enzymatic defense against nitrosative stress. J Biol Chem. 2003; 278(12):10816-23. DOI: 10.1074/jbc.M212990200. View

14.

Contreras V, Salles J, Thomas N, Morel C, Goldenberg S . In vitro differentiation of Trypanosoma cruzi under chemically defined conditions. Mol Biochem Parasitol. 1985; 16(3):315-27. DOI: 10.1016/0166-6851(85)90073-8. View

15.

Babior B . The respiratory burst of phagocytes. J Clin Invest. 1984; 73(3):599-601. PMC: 425058. DOI: 10.1172/JCI111249. View

16.

Stempin C, Garrido V, Dulgerian L, Cerban F . Cruzipain and SP600125 induce p38 activation, alter NO/arginase balance and favor the survival of Trypanosoma cruzi in macrophages. Acta Trop. 2008; 106(2):119-27. DOI: 10.1016/j.actatropica.2008.02.004. View

17.

Atwood 3rd J, Weatherly D, Minning T, Bundy B, Cavola C, Opperdoes F . The Trypanosoma cruzi proteome. Science. 2005; 309(5733):473-6. DOI: 10.1126/science.1110289. View

18.

Nathan C, Shiloh M . Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc Natl Acad Sci U S A. 2000; 97(16):8841-8. PMC: 34021. DOI: 10.1073/pnas.97.16.8841. View

19.

Castro L, Alvarez M, Radi R . Modulatory role of nitric oxide on superoxide-dependent luminol chemiluminescence. Arch Biochem Biophys. 1996; 333(1):179-88. DOI: 10.1006/abbi.1996.0379. View

20.

Lodge R, Diallo T, Descoteaux A . Leishmania donovani lipophosphoglycan blocks NADPH oxidase assembly at the phagosome membrane. Cell Microbiol. 2006; 8(12):1922-31. DOI: 10.1111/j.1462-5822.2006.00758.x. View