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* Institut für Virologie, AG Parasitologie, Philipps University, Marburg, Germany;
Instituto René Rachou, Fundaçao Oswaldo Cruz, Belo Horizonte, Brazil;
Department of Microbiology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil;
Fachbereich Chemie, University of Konstanz, Konstanz, Germany;
¶ Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA;
|| Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Brazil; and
# Unité de Glycobiologie Structurale et Fonctionnelle Unité Mixte de Recherche, Centre National de la Recherche Scientifique/Université des Sciences et Technologies de Lille No. 8576–Institut Fédératif de Recherche 118, Villeneuve D’Ascq, France
GPIs isolated from Toxoplasma gondii, as well as a chemically synthesized GPI lacking the lipid moiety, activated a reporter gene in Chinese hamster ovary cells expressing TLR4, while the core glycan and lipid moieties cleaved from the GPIs activated both TLR4- and TLR2-expressing cells. MyD88, but not TLR2, TLR4, or CD14, is absolutely needed to trigger TNF-
production by macrophages exposed to T. gondii GPIs. Importantly, TNF- response to GPIs was completely abrogated in macrophages from TLR2/4-double-deficient mice. MyD88–/– mice were more susceptible to death than wild-type (WT), TLR2–/–, TLR4–/–, TLR2/4–/–, and CD14–/– mice infected with the ME-49 strain of T. gondii. The cyst number was higher in the brain of TLR2/4–/–, but not TLR2–/–, TLR4–/–, and CD14–/–, mice, as compared with WT mice. Upon infection with the ME-49 strain of T. gondii, we observed no decrease of IL-12 and IFN-
production in TLR2-, TLR4-, or CD14-deficient mice. Indeed, splenocytes from T. gondii-infected TLR2–/– and TLR2/4–/– mice produced more IFN- than cells from WT mice in response to in vitro stimulation with parasite extracts enriched in GPI-linked surface proteins. Together, our results suggest that both TLR2 and TLR4 receptors may participate in the host defense against T. gondii infection through their activation by the GPIs and could work together with other MyD88-dependent receptors, like other TLRs or even IL-18R or IL-1R, to obtain an effective host response against T. gondii infection.
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 Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie, the Stiftung P.E. Kempkes, the Hessisches Ministerium für Wissenschaft und Kunst, the Deutscher Akademischer Austauschdienst, the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brazil), Fundação de Amparo à Pesquisa de Minas Gerais (EDT 2400/03 and EDT 24000), National Institutes of Health (1RO1AI071319-01), the Ludwig Institute For Cancer Research, the Millennium Institute for Technology and Vaccine Development–Conselho Nacional de Desenvolvimento Científico e Tecnológico (Conselho Nacional de Pesquisas (CNPq)). M.A.C. and R.T.G. are Research Fellows from CNPq.
2 Address correspondence and reprint requests to Dr. Françoise Debierre-Grockiego, Institut für Virologie, AG Parasitologie, Philipps University, Hans-Meerwein-Strasse 2, D-35043 Marburg, Germany. E-mail address: debierre{at}staff.uni-marburg.de
3 F.D.-G. and M.A.C. contributed equally to this work.
4 Current address: Altana Pharma Deutschland GmbH, Moltkestrasse 4, D-78467 Konstanz, Germany.
5 R.T.G. and R.T.S. contributed equally to this work.
6 Abbreviations used in this paper: CHO, Chinese hamster ovary; WT, wild type; TLC, thin-layer chromatography.
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