title: Caspase inhibition reduces lymphocyte apoptosis and improves host immune responses to Trypanosoma cruzi infection.
abstract: In experimental Chagas' disease, lymphocytes from mice infected with Trypanosoma cruzi show increased apoptosis in vivo and in vitro. Treatment with a pan-caspase blocker peptide inhibited expression of the active form of effector caspase-3 in vitro and rescued both B and T cells from cell death. Injection of the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone, but not a control peptide, reduced parasitemia and lymphocyte apoptosis in T. cruzi-infected mice. Moreover, treatment with caspase inhibitor throughout acute infection increased the absolute numbers of B and T cells in the spleen and lymph nodes, without affecting cell infiltrates in the heart. Following treatment, we found increased accumulation of memory/activated CD4 and CD8 T cells, and secretion of IFN-gamma by splenocytes stimulated with T. cruzi antigens. Caspase inhibition in the course of infection reduced the intracellular load of parasites in peritoneal macrophages, and increased the production of TNF-alpha and nitric oxide upon activation in vitro. Our results indicate that inhibition of caspases with a pan-caspase blocker peptide improves protective type-1 immune responses to T. cruzi infection. We suggest that mechanisms of apoptosis are potential therapeutic targets in Chagas' disease.
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Silva
authors.forename: Landi V C
authors.initials: LV
authors.lastname: Guillermo
authors.forename: Flávia L
authors.initials: FL
authors.lastname: Ribeiro-Gomes
authors.forename: Juliana
authors.initials: J
authors.lastname: De Meis
authors.forename: Marise P
authors.initials: MP
authors.lastname: Nunes
authors.forename: Juliana F V
authors.initials: JF
authors.lastname: Senra
authors.forename: Milena B P
authors.initials: MB
authors.lastname: Soares
authors.forename: George A
authors.initials: GA
authors.lastname: DosReis
authors.forename: Marcela F
authors.initials: MF
authors.lastname: Lopes
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D061945:Caspase Inhibitors; D014355:Chagas Disease / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D014349:Trypanosoma cruzi / Q000276:immunology*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; C426824:benzyloxycarbonyl-valyl-alanyl-(methyl)aspartic acid fluoromethyl ketone