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* Laboratory of Immunoregulation and Microbiology and
Laboratory of Immunoparasitology, Centro de Pesquisa Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador-Bahia, Brazil;
Laboratory of Immunology and Infectious Diseases, Microbiology and Parasitology Department, Federal University of Santa Catarina, Florianópolis-Santa Catarina, Brazil;
Institute for Investigation in Immunology-iii, São Paulo, Brazil; and
¶ Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé 872, Centre de Recherche des Cordeliers and
|| INSERM, Unité 365, Institut Curie, Paris, France
Type I IFNs (IFN-
/β) have only recently gained considerable attention as immunomodulators in nonviral infectious diseases. IFN-β has been shown to protect, in a NO-dependent manner, against murine Old World leishmaniasis caused by Leishmania major, but data in New World leishmaniasis are lacking. We found that IFN-β dose-dependently increases parasite burden in Leishmania amazonensis- as well as Leishmania braziliensis-infected human macrophages, independent of endogenous or exogenous NO. However, IFN-β significantly reduced superoxide release in Leishmania-infected as well as uninfected human macrophages. This decrease in superoxide production was paralleled by a significant IFN-β-mediated increase in superoxide dismutase 1 (SOD1) protein levels. Additionally, IFN-β inhibition of leishmanicidal activity was mimicked by SOD1 and antagonized by either pharmacological or small interfering RNA-mediated inhibition of SOD1. Finally, pronounced SOD1 expression in situ was demonstrated in biopsies from New World cutaneous leishmaniasis patients. These findings reveal a hitherto unknown IFN-β/SOD1 axis in Leishmania infection and suggest that inhibition of SOD-associated pathways could serve as strategy in the treatment of L. amazonensis as well as L. braziliensis infection, major human pathogens.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Institut National de la Santé et de la Recherche Médicale/Fundação Oswaldo Cruz (INSERM/FIOCRUZ) Collaborative Program, Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq) (A.B. and M.B.-N. are CNPq senior investigators), Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES), Programa Institucional de Bolsas de Iniciação Científica (PIBIC)-FIOCRUZ, and the Alban Program, European Union Program of High Level Scholarships for Latin America, scholarship no. E06D103200BR.
2 Address correspondence and reprint requests to Dr. Johan Van Weyenbergh, Fundação Oswaldo Cruz, Centro de Pesquisa Gonçalo Moniz (CPqGM)-Laboratório Integrado de Microbiologia e Imunoregulação, Rua Waldemar Falcão 121, 40295-001 Salvador-BA, Brazil. E-mail address: johan{at}bahia.fiocruz.br
3 Abbreviations used in this paper: L-NMMA, NG-monomethyl-L-arginine; DETC, diethyldithiocarbamate; iNOS, inducible NO synthase; siRNA, small interfering RNA; SNP, sodium nitroprusside; SOD, superoxide dismutase.
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