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Role of Effector Molecules in Pyroptosis and Cellular Lysis in the Regulation of Metabolism and Control of Toxoplasma gondii Infection

Grant number: 23/16013-6
Support Opportunities:Regular Research Grants
Duration: March 01, 2024 - February 28, 2026
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Karina Ramalho Bortoluci
Grantee:Karina Ramalho Bortoluci
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

The inflammasomes are multiprotein cytoplasmic complexes that play a crucial role in the immune response, activating caspase-1 and promoting the cleavage of pro-IL-1², pro-IL-18, and Gasdermin-D (GSDMD). GSDMD, by forming pores in the cell membrane, leads to the release of active forms of IL-1² and IL-18, triggering cell death through pyroptosis, which is associated with the control of intracellular pathogens. Recently, it has been demonstrated that cellular lysis during inflammatory cell death processes is not a passive event but is molecularly regulated by the molecule Ninjurin-1 (NINJ-1), with its role in infectious processes still not fully understood. Although inflammasome activation is associated with the control of T. gondii infection, the specific role of pyroptosis and cellular lysis, especially in cells of the Central Nervous System (CNS) where the protozoan persists in cyst form, requires a deeper understanding. During infections, macrophages and glial cells of the CNS undergo metabolic reprogramming, prioritizing aerobic glycolysis and interrupting the Krebs cycle. This process is closely linked to post-transcriptional changes in GSDMD, highlighting the interconnection between events. Pathogens such as T. gondii can induce metabolic modifications in host cells as an escape mechanism, emphasizing the importance of understanding the influence of inflammasome activation and pyroptosis on cellular metabolism alteration. This study aims to investigate the influence of pyroptosis effector molecules (GSDMD) and cellular lysis (NINJ-1) on metabolism and the control of T. gondii infection in macrophages and glial cells of the CNS, providing significant contributions to the understanding of underlying mechanisms in the pathogen-host interaction across different cell types. (AU)

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