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Interaction between inflammasomes in the control of Trypanosoma Cruzi infection

Grant number: 17/18766-0
Support type:Scholarships in Brazil - Master
Effective date (Start): January 01, 2018
Effective date (End): July 31, 2019
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Karina Ramalho Bortoluci
Grantee:Felipe Daniel Cardoso
Home Institution: Centro de Terapia Celular e Molecular. Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Inflammasomes are high-molecular-weight multiprotein complexes present in the cell cytosol. Different inflammasomes can be assembled, and vary according to their protein composition and the nature of the ligands. However, despite this diversity, the central effector mechanism of the activated inflammasomes is the conversion of the pro-caspase-1 in caspase-1. In turn, caspase-1 cleaves gasdermin D, and the cytokines pro-IL-1² and pro-IL-18 in their active forms, IL-1² and IL-18. IL-1² and IL-18 are potent pro-inflammatory cytokines, while gasdermin D cleavage induces the pro-inflammatory cell death pyroptosis. Among the inflammasomes, those formed by the receptor proteins NLRP3 and NLRC4 are the most studied. Inflammasomes assembled by NLRP3 respond to alterations in the intracellular environment caused by a diversity of sterile and non-sterile stimuli. In contrast, the NLRC4 inflammasomes are formed mainly in response to flagellin and bacterial secretion systems stimuli. Previously, our group demonstrated the role of NLRP3 in the resistance to Trypanosoma cruzi infection. We showed that its activation is dependent on the activity of cathepsins, which we also described as being involved in the NLRC4 inflammasome modulation. Recent studies have shown that distinct inflammasomes are able to interact with one another, directly or not, in response to specific stimuli. Interestingly, there are no studies evaluating the role of the inflammasome NLRC4 against protozoal infections. Therefore, the main proposal of this project is to evaluate the role of the NLRC4 inflammasome in response to T. cruzi infection, investigating the importance of its protein components and possible association with the inflammasome NLRP3.