title: TcI Isolates of Trypanosoma cruzi Exploit the Antioxidant Network for Enhanced Intracellular Survival in Macrophages and Virulence in Mice.
abstract: Trypanosoma cruzi species is categorized into six discrete typing units (TcI to TcVI) of which TcI is most abundantly noted in the sylvatic transmission cycle and considered the major cause of human disease. In our study, the TcI strains Colombiana (COL), SylvioX10/4 (SYL), and a cultured clone (TCC) exhibited different biological behavior in a murine model, ranging from high parasitemia and symptomatic cardiomyopathy (SYL), mild parasitemia and high tissue tropism (COL), to no pathogenicity (TCC). Proteomic profiling of the insect (epimastigote) and infective (trypomastigote) forms by two-dimensional gel electrophoresis/matrix-assisted laser desorption ionization-time of flight mass spectrometry, followed by functional annotation of the differential proteome data sets (≥2-fold change, P < 0.05), showed that several proteins involved in (i) cytoskeletal assembly and remodeling, essential for flagellar wave frequency and amplitude and forward motility of the parasite, and (ii) the parasite-specific antioxidant network were enhanced in COL and SYL (versus TCC) trypomastigotes. Western blotting confirmed the enhanced protein levels of cytosolic and mitochondrial tryparedoxin peroxidases and their substrate (tryparedoxin) and iron superoxide dismutase in COL and SYL (versus TCC) trypomastigotes. Further, COL and SYL (but not TCC) were resistant to exogenous treatment with stable oxidants (H2O2 and peroxynitrite [ONOO(-)]) and dampened the intracellular superoxide and nitric oxide response in macrophages, and thus these isolates escaped from macrophages. Our findings suggest that protein expression conducive to increase in motility and control of macrophage-derived free radicals provides survival and persistence benefits to TcI isolates of T. cruzi.
authors.affiliation: Instituto de Patologia Experimental, Universidad Nacional de Salta Consejo, Nacional de Investigaciones Científicas y Técnicas (IPE-UNSa, CONICET), Salta, Argentina mpzago@conicet.gov.ar nigarg@utmb.edu.
authors.forename: María Paola
authors.initials: MP
authors.lastname: Zago
authors.affiliation: Biomolecular Resource Facility, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Yashoda M
authors.initials: YM
authors.lastname: Hosakote
authors.affiliation: Department of Pathology, School of Medicine, University of Texas Medical Branch Galveston, Galveston, Texas, USA.
authors.forename: Sue-Jie
authors.initials: SJ
authors.lastname: Koo
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Monisha
authors.initials: M
authors.lastname: Dhiman
authors.affiliation: Unidad de Biología Molecular, Institut Pasteur de Montevideo, Montevideo, Uruguay.|Departmento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Piñeyro
authors.affiliation: Unidad de Biología Molecular, Institut Pasteur de Montevideo, Montevideo, Uruguay.|Sección Genética, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
authors.forename: Adriana
authors.initials: A
authors.lastname: Parodi-Talice
authors.affiliation: Instituto de Patologia Experimental, Universidad Nacional de Salta Consejo, Nacional de Investigaciones Científicas y Técnicas (IPE-UNSa, CONICET), Salta, Argentina.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Basombrio
authors.affiliation: Unidad de Biología Molecular, Institut Pasteur de Montevideo, Montevideo, Uruguay.|Departmento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
authors.forename: Carlos
authors.initials: C
authors.lastname: Robello
authors.affiliation: Department of Pathology, School of Medicine, University of Texas Medical Branch Galveston, Galveston, Texas, USA mpzago@conicet.gov.ar nigarg@utmb.edu.|Department of Microbiology and Immunology, School of Medicine, University of Texas Medical Branch, Galveston, Texas, USA.|Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Nisha J
authors.initials: NJ
authors.lastname: Garg
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D014355:Chagas Disease / Q000235:genetics* / Q000378:metabolism / Q000469:parasitology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008018:Life Cycle Stages / Q000187:drug effects / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism* / Q000469:parasitology; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018512:Parasitemia / Q000235:genetics / Q000378:metabolism / Q000469:parasitology; D010544:Peroxidases / Q000235:genetics / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000494:pharmacology; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity*
chemical_list: D000975:Antioxidants; D003598:Cytoskeletal Proteins; D024101:Mitochondrial Proteins; D015800:Protozoan Proteins; C114110:tryparedoxin; D030421:Peroxynitrous Acid; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D010544:Peroxidases; C110959:tryparedoxin peroxidase; D013482:Superoxide Dismutase