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ACTIVATION OF TLR2 AND TLR4 BY GLYCOSYLPHOSPHATIDYLINOSITOLS DERIVED FROM TOXOPLASMA GONDII
Autor
Afiliación
Institut fur Virologie. AG Parasitologie. Philipps University. Marburg, Germany
Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brazil.
Institut fur Virologie. AG Parasitologie. Philipps University. Marburg, Germany
Institut fur Virologie. AG Parasitologie. Philipps University. Marburg, Germany
Institut fur Virologie. AG Parasitologie. Philipps University. Marburg, Germany
Fundação Oswaldo Cruz. Instituto Rene´ Rachou. Belo Horizonte, MG, Brazil
Department of Microbiology. Biological Sciences Institute.Federal University of Minas Gerais. Belo Horizonte, MG, Brazil
Fachbereich Chemie. University of Konstanz. Konstanz, Germany
Fachbereich Chemie. University of Konstanz. Konstanz, Germany
Division of Infectious Disease and Immunology. Department of Medicine. University of Massachusetts Medical School. Worcester, MA
Fundacao Oswaldo Cruz. Instituto Rene´ Rachou. Belo Horizonte, MG, Brazil/Division of Infectious Disease and Immunology. Department of Medicine. University of Massachusetts Medical School. Worcester, MA
Unite de Glycobiologie Structurale et Fonctionnelle Unite´ Mixte de Recherche. Centre National de la Recherche Scientifique/Universite´ des Sciences et Technologies de Lille No. 8576 –Institut Federatif de Recherche 118, Villeneuve D’Ascq, France
Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brazil.
Institut fur Virologie. AG Parasitologie. Philipps University. Marburg, Germany
Institut fur Virologie. AG Parasitologie. Philipps University. Marburg, Germany
Institut fur Virologie. AG Parasitologie. Philipps University. Marburg, Germany
Fundação Oswaldo Cruz. Instituto Rene´ Rachou. Belo Horizonte, MG, Brazil
Department of Microbiology. Biological Sciences Institute.Federal University of Minas Gerais. Belo Horizonte, MG, Brazil
Fachbereich Chemie. University of Konstanz. Konstanz, Germany
Fachbereich Chemie. University of Konstanz. Konstanz, Germany
Division of Infectious Disease and Immunology. Department of Medicine. University of Massachusetts Medical School. Worcester, MA
Fundacao Oswaldo Cruz. Instituto Rene´ Rachou. Belo Horizonte, MG, Brazil/Division of Infectious Disease and Immunology. Department of Medicine. University of Massachusetts Medical School. Worcester, MA
Unite de Glycobiologie Structurale et Fonctionnelle Unite´ Mixte de Recherche. Centre National de la Recherche Scientifique/Universite´ des Sciences et Technologies de Lille No. 8576 –Institut Federatif de Recherche 118, Villeneuve D’Ascq, France
Resumen en ingles
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-a production by macrophages exposed to T. gondii GPIs. Importantly, TNF-a 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-gamma production in TLR2-, TLR4-, or CD14-deficient mice. Indeed, splenocytes from T. gondii-infected TLR2(-/-) and TLR2/4(-/-) mice produced more IFN-gamma 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-IR, to obtain an effective host response against T. gondii infection
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