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CUTTING EDGE |
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* Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil;
Laboratório de Imunopatologia, CPqRR, FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil
Activation of innate immune cells by Trypanosoma cruzi-derived molecules such as GPI anchors and DNA induces proinflammatory cytokine production and host defense mechanisms. In this study, we demonstrate that DNA from T. cruzi stimulates cytokine production by APCs in a TLR9-dependent manner and synergizes with parasite-derived GPI anchor, a TLR2 agonist, in the induction of cytokines by macrophages. Compared with wild-type animals, T. cruzi-infected Tlr9–/– mice displayed elevated parasitemia and decreased survival. Strikingly, infected Tlr2–/–Tlr9–/– mice developed a parasitemia equivalent to animals lacking MyD88, an essential signaling molecule for most TLR, but did not show the acute mortality displayed by MyD88–/– animals. The enhanced susceptibility of Tlr9–/– and Tlr2–/–Tlr9–/– mice was associated with decreased in vivo IL-12/IFN-
responses. Our results reveal that TLR2 and TLR9 cooperate in the control of parasite replication and that TLR9 has a primary role in the MyD88-dependent induction of IL-12/IFN- synthesis during infection with T. cruzi.
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 R.T.G. and C.R. are Conselho Nacional de Pesquisas (Brazil) fellowship recipients.
2 Address correspondence and reprint requests to Dr. André Báfica, Immunobiology Section, National Institute of Allergy and Infectious Diseases–Laboratory of Parasitic Diseases, 50 NIH South Dr, Room 6146, Bethesda, MD 20892. E-mail address: abafica{at}niaid.nih.gov or Dr. Ricardo T. Gazzinelli, Lab. de Imunopatologia, Centro de Pequisas Rene Rachou–Fundaçao Oswaldo Cruz, Av. Augusto de Lima 1715, B. Horizonte, MG 30190-002. E-mail address: ritoga{at}cpqrr.fiocruz.br
3 R.T.G. and A.S. contributed equally to this study.
4 Abbreviations used in this paper: DC, dendritic cells, BMM, bone marrow-derived macrophages; BMDC, bone marrow-derived dendritic cell; KO, knockout; WT, wild type.
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