RRC ID 18092
著者 Paiva CN, Feijó DF, Dutra FF, Carneiro VC, Freitas GB, Alves LS, Mesquita J, Fortes GB, Figueiredo RT, Souza HS, Fantappié MR, Lannes-Vieira J, Bozza MT.
タイトル Oxidative stress fuels Trypanosoma cruzi infection in mice.
ジャーナル J Clin Invest
Abstract 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.
巻・号 122(7)
ページ 2531-42
公開日 2012-7-1
DOI 10.1172/JCI58525
PII 58525
PMID 22728935
PMC PMC3386808
MeSH Animals Antioxidants / metabolism Antiparasitic Agents / pharmacology Antiparasitic Agents / therapeutic use Cation Transport Proteins / genetics Cation Transport Proteins / metabolism Chagas Disease / drug therapy Chagas Disease / parasitology* Ferritins / genetics Ferritins / metabolism Ferrous Compounds / pharmacology Heart / parasitology Heme Oxygenase-1 / antagonists & inhibitors Heme Oxygenase-1 / genetics Heme Oxygenase-1 / metabolism Host-Parasite Interactions Iron / metabolism Macrophages, Peritoneal / drug effects Macrophages, Peritoneal / enzymology Macrophages, Peritoneal / parasitology Mice Mice, Inbred C57BL Muscle, Skeletal / parasitology NF-E2-Related Factor 2 / genetics NF-E2-Related Factor 2 / metabolism Oxidative Stress* Parasitemia / drug therapy Parasitemia / parasitology* Protoporphyrins / pharmacology Protoporphyrins / therapeutic use Reactive Oxygen Species / metabolism Receptors, Immunologic / metabolism Respiratory Burst Trypanosoma cruzi / drug effects Trypanosoma cruzi / physiology*
IF 11.864
引用数 82
WOS 分野 MEDICINE, RESEARCH & EXPERIMENTAL
リソース情報
実験動物マウス RBRC01390