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Influence of the interaction between Gasdermina-D and HIF-1 alfa in the control of Toxoplasma gondii infection

Grant number: 23/10401-4
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): December 01, 2023
Effective date (End): July 31, 2025
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Karina Ramalho Bortoluci
Grantee:Rafael Queiroz de Souza
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Inflammasomes are multiprotein cytoplasmic complexes capable of activating caspase-1, which in turn cleaves pro-IL-1 beta, pro-IL-18 and Gasdermin-D (GDSMD). GSDMD is able to form pores in the cell membrane resulting in the secretion of active forms of IL-1 beta and IL-18 and induction of cell death by pyroptosis. Several inflammasomes are activated during T. gondii infection, resulting in the induction of pyroptosis and secretion of IL-1 beta and IL-18, important for the control of this protozoan. Macrophages, which play an important role in restricting T. gondii, present a metabolic reprogramming aimed at aerobic glycolysis and interruption of the Krebs cycle. Activation of the transcription factor HIF-1 alpha is involved in this metabolic reprogramming and has been associated with activation of inflammasomes under hypoxic conditions. In T. gondii infection, the transcription factor HIF-1 alpha is stabilized and activated, impacting the growth and survival of the pathogen. Despite the evidence of the role of HIF-1 alpha in the activation of inflammasomes and induction of pyroptosis, little is known about the influence of inflammasomes and their effector mechanisms in the stabilization of HIF-1 alpha and metabolic alteration of macrophages in the face of intracellular infections. Thus, this work seeks to study the influence of GSDMD on macrophage immunometabolism, especially on the stabilization of HIF-1 alpha and its impact on resistance against T. gondii infection, thus contributing to the understanding of the mechanisms involved in the host-pathogen interaction .

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