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Interaction of TLR2 and TLR4 Nglycans with the Toxoplasma gondii microneme proteins triggers host cells activation

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Author(s):
Flávia Costa Mendonça Natividade
Total Authors: 1
Document type: Doctoral Thesis
Press: Ribeirão Preto.
Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
Defense date:
Examining board members:
Maria Cristina Roque Antunes Barreira; Lucia Helena Faccioli; Luis Lamberti Pinto da Silva; Adriane Regina Todeschini
Advisor: Maria Cristina Roque Antunes Barreira
Abstract

Toxoplasmosis is the disease caused by the protozoan Toxoplasma gondii, it may generate severe disease in fetuses and immunocompromised individuals. T. gondii is eurixene and can be able to invade and develop within any nucleated cell of warm-blooded animals. Some organelles from T.gondii release several molecules involved in adhesion and host cell invasion process. Among these secretory products, are also included those released by micronemes. The micronemes proteins are found in association on the surface of tachyzoite, resulting in the formation of complexes, MIC1/MIC4/MIC6. The complex, anchored to the parasite membrane through MIC6, interacts with cells through the MIC1 and MIC4 carbohydrate recognition domains (CRD), which bind to glycans with terminal sialic acid and beta-galactose, respectively. We verified that either recombinant counterparts of MIC1 (rMIC1) and MIC4 (rMIC4), interact with through their CRDs with Toll-like (TLR) 2 and TLR4 receptors and activate host cells, leading to the production (IL-) 12. The importance of IL-12 is evident since it is crucial to the differentiation of CD4 interferon-? producers, this cytokine that controls the replication of the parasite and limits the infection. In the present study, the intracellular pathways triggered by rMIC1 and rMIC4 to produce cytokines by macrophages were characterized. The recognition of N-glycans from ectodomains of TLR2 and TLR4 by rMIC1 and rMIC4, induce the recruitment of adapter molecules to TIR domains (Toll / interleukin-1 receptor) that allow the establishment of signaling pathways dependent on TAK1 phosphorylation (Transforming growth factor-?-activated kinase 1), p38 MAPK (Mitogen-activated protein kinase p38) and the translocation of NF-?B (Nuclear factor ?B) to the nucleus and consequent induction of pro-inflammatory cytokines. Also, the interaction of rMIC1 or rMIC4 with TLR2 or TLR4 directs the internalization of both receptors and, from the endosomal compartments, initiates signal transduction that culminates in the activation of the transcription factors IRF3 and IRF7 (Interferon regulatory factor) and the production of interleukin 10. Despite the function of assisting the activation of TLRdependent pathways, we have found that CD14 and CD36 (cluster of differentiation 14 and 36) is not essential for IL-12 production in response to rMIC1 and rMIC4 stimuli.Besides, preliminary studies show that rMIC1 and rMIC4 are potential inducers of macrophages tolerance to rMICs and endotoxins. Our study allows concluding that rMIC1 and rMIC4 act as agonists of TLR2 and TLR4 and promote the activation of signaling pathways similar to those activated by lipopeptides or bacterial lipopolysaccharides. Our results contribute to the understanding of survival strategies and the generation of the immune response against T.gondii. (AU)

FAPESP's process: 14/13324-1 - Interaction of microneme proteins of Toxoplasma gondii with N-linked glycans of TLR4: effects on innate immunity
Grantee:Flávia Costa Mendonça Natividade
Support type: Scholarships in Brazil - Doctorate