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Characterization of TgMIC1 and TgMIC4 immunomodulatory potential: analysis of pleiotropic effect and repercussions on adaptive immunity

Grant number: 14/05362-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): June 01, 2014
Effective date (End): May 31, 2015
Field of knowledge:Biological Sciences - Biology
Principal Investigator:Maria Cristina Roque Antunes Barreira
Grantee:André Luiz Vieira Zorzetto Fernandes
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:13/04088-0 - Lectin from pathogens, AP.TEM

Abstract

Lectins from Toxoplasma gondii studied by our group, TgMIC1 and TgMIC4 are described by recognizing, respectively, sialic acid (TgMIC1) and ²-galactosides (TgMIC4). These lectins are capable of activating cells of innate immune system, such as macrophages and dendritic cells, inducing the production of proinflammatory cytokines. We have demonstrated that cell activation is dependent of Toll like receptors 2 and 4, being TLR4 more important for the success of the interaction.Studies concerning lectins from pathogens which we have been developing are, in most part, motivated by demonstrations that protein-carbohydrate interactions stimulate cells of innate and adaptive immune system, acting as immunomodulators. This is the caso of some mammalian lectins, like galectin-3, and plants, such as ArtinM, obtained from the seeds of Artocarpus heterophyllus.The molecule of ArtinM is organized as a homotetramer. Each subunit that composes the tetramer contains a carbohydrate-recognizing domain (CRD) with two subsites. The primary subsite recognizes with high affinity the trimmanoside Man± 1-3 [Man± 1-6] Man, which constitute the core of all N-glycans, while the secondary subsite binds to GlcNAc residues, that extend the oligosaccharide chain from Man6. These extended N-glycans are part located on several cell surface receptors, making thse binding targets of ArtinM. Such interaction may trigger different cellular responses. So, the recognition of N-glycans on TLR2 surface on antigen presenting cells (macrophages and dendritic cells) results in cell activation and production of high levels of IL-12, cytokine that stimulates lymphocytes to secrete IFN-³ and promotes the development of Th1 bias immunity. Our group has verified that besides N-glycans from TLR2, the co-receptor CD14 also represents an important target for ArtinM interaction on macrophage surface. CD14 absence drastically compromises the induction of inflammatory profile, increase of phagocytic and migratory activity, NF-kB e MAPK pathway activation, STAT1 and SOCS3 gene expression, and M1 polarization after lectin stimulus. Preliminary assays revealed that TgMIC1 was unable of inducing IL-12 production by CD14KO macrophages, suggesting a possible dependence between this lectin and co-receptor.Recently, our group reported that ArtinM interacts with N-glycans associated with ³ chain from CD3 receptor, exerting an activating role on T CD4+ lymphocytes, manifested by CD25 and CTLA-4 increased expression and production of IL-2, IFN-³, IL-6 and IL-17, cytokines that define the fact that naïve T CD4+ cells differentiates into Th1 and Th17 cells undes ArtinM stimulus. In this manner, it is possible that lectins from pathogens, like TgMIC1 and TgMIC4 from Toxoplasma gondii, are capable of interacting with several types of cells, besides the ones already characterized (macrophages and dendritic cells), and this interaction may have important results on parasitism and infection. Also, others glycosilated molecules may have an essential role in the induction of the observed response by TgMIC1 and TgMIC4. Consequently, this study would allow the characterization of new mechanisms involving the interaction between T. gondii and the innate immune system.