Experimental chemotherapy against Trypanosoma cruzi infection: essential role of endogenous interferon-gamma in mediating parasitologic cure.
Studies in humans and in experimental models suggest the involvement of the immune system for efficacy of drug treatment against protozoan parasites. This study tested this hypothesis by using various cytokine and inducible nitric oxide synthase (iNOS) knockout (KO) mice infected with Trypanosoma cruzi and treated with benznidazole. In contrast with the 100% parasitologic cure rate achieved in wild-type animals, benznidazole failed to cure 100%, 42%, 35%, and 28% of interferon-gamma, interleukin-12 (protein 40), protein 55-tumor necrosis factor receptor, and iNOS KO mice, respectively. These results suggest that activation of the immune system by the parasite and endogenous interferon-gamma play a major role in the efficacy of benznidazole against infection with T. cruzi.
Romanha
Alvaro J
AJ
Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
Alves
Rosana O
RO
Murta
Silvane M F
SM
Silva
João S
JS
Ropert
Catherine
C
Gazzinelli
Ricardo T
RT
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D014355:Chagas Disease / Q000188:drug therapy* / Q000276:immunology* / Q000469:parasitology; D005260:Female; D017353:Gene Deletion; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009593:Nitroimidazoles / Q000627:therapeutic use*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I; D013997:Time Factors; D014344:Trypanocidal Agents / Q000627:therapeutic use; D014349:Trypanosoma cruzi / Q000276:immunology*
D015703:Antigens, CD; D009593:Nitroimidazoles; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014344:Trypanocidal Agents; D018664:Interleukin-12; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C009999:benzonidazole