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Title

The lectin-specific activity of Toxoplasma gondii microneme proteins 1 and 4 binds Toll-like receptor 2 and 4 N-glycans to regulate innate immune priming

Authors
Sardinha-Silva, Aline
Mendonça-Natividade, Flávia C
Pinzan, Camila F
Lopes, Carla D
Costa, Diego L
Fernandes, Fabricio F
Zorzetto-Fernandes, André L V
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Published in PLOS Pathogens. 2019, vol. 15, no. 6, p. e1007871
Abstract Infection of host cells by Toxoplasma gondii is an active process, which is regulated by secretion of microneme (MICs) and rhoptry proteins (ROPs and RONs) from specialized organelles in the apical pole of the parasite. MIC1, MIC4 and MIC6 assemble into an adhesin complex, secreted on the parasite surface and function to promote infection competency. MIC1 and MIC4 are known to bind terminal sialic acid residues and galactose residues, respectively and to induce IL-12 production from splenocytes. Here we show that rMIC1- and rMIC4-stimulated dendritic cells and macrophages to produce proinflammatory cytokines, and they do so by engaging TLR2 and TLR4. This process depends on sugar recognition, since point mutations in the carbohydrate-recognition domains (CRD) of rMIC1 and rMIC4 inhibit innate immune cells activation. HEK cells transfected with TLR2 glycomutants were selectively unresponsive to MICs. Following in vitro infection, parasites lacking MIC1 or MIC4, as well as expressing MIC proteins with point mutations in their CRD, failed to induce wild-type (WT) levels of IL-12 secretion by innate immune cells. However, only MIC1 was shown to impact systemic levels of IL-12 and IFN-γ in vivo. Together, our data show that MIC1 and MIC4 interact physically with TLR2 and TLR4 N-glycans to trigger IL-12 responses, and MIC1 is playing a significant role in vivo by altering T. gondii infection competency and murine pathogenesis.
Identifiers
PMID: 31226171
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Article (Published version) (6.8 MB) - public document Free access
Structures
Research group Biologie d'un parasite intracellulaire obligatoire (773)
Project FNS: 310030B_166678
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(ISO format)
SARDINHA-SILVA, Aline et al. The lectin-specific activity of Toxoplasma gondii microneme proteins 1 and 4 binds Toll-like receptor 2 and 4 N-glycans to regulate innate immune priming. In: PLOS Pathogens, 2019, vol. 15, n° 6, p. e1007871. https://archive-ouverte.unige.ch/unige:119876

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Deposited on : 2019-06-24

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