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* Department of Parasitology and Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil;
René Rachou Institute, Oswaldo Cruz Foundation, Belo Horizonte, Minas Gerais, Brazil; and
Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655
TLR9 is critical in parasite recognition and host resistance to experimental infection with Trypanosoma cruzi. However, no information is available regarding nucleotide sequences and cellular events involved on T. cruzi recognition by TLR9. In silico wide analysis associated with in vitro screening of synthetic oligonucleotides demonstrates that the retrotransposon VIPER elements and mucin-like glycoprotein (TcMUC) genes in the T. cruzi genome are highly enriched for CpG motifs that are immunostimulatory for mouse and human TLR9, respectively. Importantly, infection with T. cruzi triggers high levels of luciferase activity under NF-
B-dependent transcription in HEK cells cotransfected with human TLR9, but not in control (cotransfected with human MD2/TLR4) HEK cells. Further, we observed translocation of TLR9 to the lysosomes during invasion/uptake of T. cruzi parasites by dendritic cells. Consistently, potent proinflammatory activity was observed when highly unmethylated T. cruzi genomic DNA was delivered to the endo-lysosomal compartment of host cells expressing TLR9. Thus, together our results indicate that the unmethylated CpG motifs found in the T. cruzi genome are likely to be main parasite targets and probably become available to TLR9 when parasites are destroyed in the lysosome-fused vacuoles during parasite invasion/uptake by phagocytes.
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 Atlantic Philanthropies and the Ludwig Institute for Cancer Research, the Millennium Institute for Technology and Vaccine Development/Conselho Nacional de Desenvolvimento Cientifico e Technologico (CNPq), Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG), and the National Institutes of Health (Grant AI071319-01). D.C.B. is supported by the World Health Organization/Special Program for Training in Tropical Diseases and FAPEMIG. R.T.G., D.C.B., S.M.R.T., and C.R. are research fellows from CNPq and FAPEMIG, respectively.
2 D.C.B. and C.R. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Ricardo T. Gazzinelli, Laboratory of Immunopathology, René Rachou Institute, Oswaldo Cruz Foundation (FIOCRUZ), Av. Augusto de Lima 1715, 30190-002 Belo Horizonte, Minas Gerais, Brazil. E-mail address: ritoga{at}cpqrr.fiocruz.br
4 Abbreviations used in this paper: ODN, oligodeoxynucleotide; BMDC, bone marrow-derived dendritic cell; DC, dendritic cell; DOTAP, 1,2-dioleoyloxy-3-(trimethylammonium)propane; RFP, red fluorescent protein; WT, wild type; YFP, yellow fluorescent protein.
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