Caspase inhibition reduces lymphocyte apoptosis and improves host immune responses to Trypanosoma cruzi infection.
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.
Silva
Elisabeth M
EM
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Guillermo
Landi V C
LV
Ribeiro-Gomes
Flávia L
FL
De Meis
Juliana
J
Nunes
Marise P
MP
Senra
Juliana F V
JF
Soares
Milena B P
MB
DosReis
George A
GA
Lopes
Marcela F
MF
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*
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; C426824:benzyloxycarbonyl-valyl-alanyl-(methyl)aspartic acid fluoromethyl ketone