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Role of pyroptosis in the control of Toxoplasma gondii infection in different cell types

Grant number: 19/13631-5
Support type:Scholarships in Brazil - Master
Effective date (Start): December 01, 2019
Effective date (End): June 30, 2021
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal researcher:Karina Ramalho Bortoluci
Grantee:Luiza Zainotti Miguel Fahur Bottino
Home Institution: Centro de Terapia Celular e Molecular. Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Toxoplasma gondii is an obligate intracellular parasite that causes Toxoplasmosis, a disease that can be fatal for immunocompromised or newborns of infected mothers. Several defense mechanisms mediated by innate immunity have already been described in resistance to the parasite, including mechanisms mediated by inflammasomes. Inflammasomes are caspase-1 activating multiprotein platforms, which are responsible for the processing of IL-1² and IL-18 cytokines and induction of pyroptosis. Pyroptosis is an extremely relevant inflammatory cell death in the context of infection control by intracellular pathogens. However, only recently have the molecular mechanisms involved in the regulation of this process been uncovered, which include the cleavage of Gasdermin D (GSDMD) by caspases-1 and -11 and raise this protein as an essential mediator of the pyroptosis triggered by canonical and non-canonical inflammasomes. Although the requirement of inflammasomes has already been described in the control of protozoal infections, there is no report on the specific contribution of pyroptosis in these processes. Thus, the project aims to evaluate the ability of T. gondii to induce pyrophosis and to verify the influence of this process on the activation of the inflammatory response and its impact on infection control. In this context, the use of GSDMD-deficient mice will allow the assessment of the susceptibility associated with the molecule in order to clarify the relevance of the pyroptosis mechanism in vivo. Finally, considering the neurotropism of the parasite, this infection model allows the investigation of these parameters not only in macrophages but also in microglia and astrocytes, allowing a comparison between the different cell types. (AU)

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