Oxidative stress fuels Trypanosoma cruzi infection in mice.
Oxidative damage contributes to microbe elimination during macrophage respiratory burst. Nuclear factor, erythroid-derived 2, like 2 (NRF2) orchestrates antioxidant defenses, including the expression of heme-oxygenase-1 (HO-1). Unexpectedly, the activation of NRF2 and HO-1 reduces infection by a number of pathogens, although the mechanism responsible for this effect is largely unknown. We studied Trypanosoma cruzi infection in mice in which NRF2/HO-1 was induced with cobalt protoporphyrin (CoPP). CoPP reduced parasitemia and tissue parasitism, while an inhibitor of HO-1 activity increased T. cruzi parasitemia in blood. CoPP-induced effects did not depend on the adaptive immunity, nor were parasites directly targeted. We also found that CoPP reduced macrophage parasitism, which depended on NRF2 expression but not on classical mechanisms such as apoptosis of infected cells, induction of type I IFN, or NO. We found that exogenous expression of NRF2 or HO-1 also reduced macrophage parasitism. Several antioxidants, including NRF2 activators, reduced macrophage parasite burden, while pro-oxidants promoted it. Reducing the intracellular labile iron pool decreased parasitism, and antioxidants increased the expression of ferritin and ferroportin in infected macrophages. Ferrous sulfate reversed the CoPP-induced decrease in macrophage parasite burden and, given in vivo, reversed their protective effects. Our results indicate that oxidative stress contributes to parasite persistence in host tissues and open a new avenue for the development of anti-T. cruzi drugs.
Laboratório de Inflamação e Imunidade, Departamento de Imunologia, Instituto de Microbiologia Professor Paulo de Góes (IMPPG), Rio de Janeiro, Brazil.
Claudia N
CN
Paiva
Daniel F
DF
Feijó
Fabianno F
FF
Dutra
Vitor C
VC
Carneiro
Guilherme B
GB
Freitas
Letícia S
LS
Alves
Jacilene
J
Mesquita
Guilherme B
GB
Fortes
Rodrigo T
RT
Figueiredo
Heitor S P
HS
Souza
Marcelo R
MR
Fantappié
Joseli
J
Lannes-Vieira
Marcelo T
MT
Bozza
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D000977:Antiparasitic Agents / Q000494:pharmacology / Q000627:therapeutic use; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D014355:Chagas Disease / Q000188:drug therapy / Q000469:parasitology*; D005293:Ferritins / Q000235:genetics / Q000378:metabolism; D005296:Ferrous Compounds / Q000494:pharmacology; D006321:Heart / Q000469:parasitology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006790:Host-Parasite Interactions; D007501:Iron / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000469:parasitology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology*; D011524:Protoporphyrins / Q000494:pharmacology / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D016897:Respiratory Burst; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000502:physiology*; D000098742:Ferroportin
D000975:Antioxidants; D000977:Antiparasitic Agents; D027682:Cation Transport Proteins; D005296:Ferrous Compounds; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C105949:Pirb protein, mouse; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; D011971:Receptors, Immunologic; D000098742:Ferroportin; C020748:ferrous sulfate; C007095:cobaltiprotoporphyrin; D005293:Ferritins; D007501:Iron; D051547:Heme Oxygenase-1