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Role of NLRP3 and NAIP-NLRC4 inflammasomes after Toxoplasma gondii infection in glial cells of the central nervous system

Grant number: 18/19252-3
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): September 01, 2020
Effective date (End): June 30, 2022
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal researcher:Karina Ramalho Bortoluci
Grantee:Marcelo Pires Amaral
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 and is responsible for causing the disease Toxoplasmosis, which can present several serious clinical manifestations and even lead immunocompromised patients to death. T. gondii is the major protozoan neurotrophism model, being widely observed in its latent form (cysts) in cells of the Central Nervous System (CNS). The control of T. gondii infection is mediated by the innate and adaptive immune response. The effector mechanisms for the control of T. gondii infection are generated from the activation of receptors/sensors of innate immunity, including inflammasomes. Inflammasomes activation, obligatory or optional recruitment - depending on the inflammasome - of the ASC adapter protein occurs, which is capable of inducing the cleavage of pro-caspase-1 in its active form caspase-1. Next, caspase-1 cleaves pro-inflammatory cytokines pro-IL-1² and pro-IL-18 in its active forms IL-1² and IL-18, as well as gasdermin D (GSDMD). The N-terminal fragment of GSDMD is inserted into the cell membrane forming pores, resulting in inflammatory cell death called pyroptosis. Recently, NLRP3 has been characterized as an important inflammasome in the control of protozoa, whereas the inflammasome NAIP-NLRC4 has been related to the control of bacterial infections, besides its role in sterile inflammations. There is no data evaluating the role of inflammasome in glial CNS cells in the context of T. gondii infection in the scientific literature. The main objective of this project is to evaluate the role of inflammasomes NLRP3 and NAIP-NLRC4, as well as its possible interaction in controlling T. gondii infection in glial cells of the CNS of mice. The characterization of the effector mechanisms mediated by the inflammasomes after T. gondii infection will shed light to the understanding of these protein complexes in different cell types and to the development of effective therapies against the parasite. (AU)