Like other parasites of the phylum Apicomplexa, Toxoplasma gondii invades host cells through a process that depends on the release of microneme proteins from intracellular organelles called micronemes (MIC). Microneme proteins 1 (TgMIC1), 4 (TgMIC4), and 6 (TgMIC6) form a complex on the surface of T. gondii. TgMIC1 and TgMIC4, are carbohydrate-binding proteins that recognize terminal sialic acid and galactose, respectively, in host cells glycans. Activation of TLRs by microbial ligands plays an important role in initiating immunity to many pathogens, including T. gondii. There is evidence that TLR1, TLR2, TLR6, and TLR4 are glycosylated proteins. Our group identified that the microneme proteins TgMIC1 and TgMIC4 are able to induce IL-12 production by APCs via activation of TLR2 and TLR4. However, the biochemical and structural physical interactions of TgMIC1 and TgMIC4 with TLRs are mostly unknown. Then, the first aim of this project is to study, at the biochemical and structural level, the way through which TgMICs activate TLRs. It was previously demonstrated that NK cells encode members of the Toll-like receptor family, such as, TLR1, TLR2, TLR3, TLR5, and TLR6. Besides, it has been showed that PAMPs can directly stimulate human and mice NK cells. Thus, our second aim is to investigate whether TgMICs interact directly with TLRs in NK cells and to evaluate the possible improvement of this response by synergic signals generated by TgMICs pre-activated cells. In general, studies involving pathogens and TLRs are performed in animal models. We believe that the direct interaction of TgMIC1 and TgMIC4 with TLR2 and TLR4, and the consequent induction of Th1 immunity, may activate defense mechanisms of humans against T. gondii. So, we intend address how human innate immune cells detect microneme proteins and respond to them. This study will lead to better comprehension of the relationship between T. gondii virulence and modulation of human immune responses.
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