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Evaluation of the role of the transcription factor HIF1alpha in the inflammasome activation and progression of Leishmania infection

Grant number: 22/14157-8
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): June 01, 2023
Effective date (End): May 31, 2025
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Dario Simões Zamboni
Grantee:Juliane Cristina Ribeiro Fernandes
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:19/11342-6 - Mechanisms and consequences of the activation of cytoplasmic receptors by intracellular pathogens, AP.TEM

Abstract

Protozoan parasites of the Leishmania genus cause leishmaniasis by establishing their replicative niche in the interior of macrophage's phagolysosomes. In this interaction, diverse responses that limit parasite growth are triggered, such as activating the multimeric protein complex inflammasome. The Nod-like receptor Pyrin domain 3 (NLRP3) inflammasome is involved in processing pro-IL-1² to IL-1² through caspase1 (CASP1) during Leishmania infection. Inflammasome activation depends on the availability of its components, regulated by the so-called first signal, which determines transcriptional activation. In contrast, the second signals, such as damage-associated molecular patterns (DAMPs), determine the oligomerization and activity of the inflammasome. The process is also highly regulated by autophagy, which can eliminate cytosolic components important for oligomerization or activation of the inflammasome. The transcription factor hypoxia-inducible factor 1± (HIF1±), associated with the pyruvate kinase M2 (PKM2), promotes the transcriptional activation of pro-IL-1², genes of the glycolytic metabolism, and genes related to autophagy. This way, HIF1± can present roles of either inducing inflammasome activity or inhibiting it by promoting autophagy. This project hypothesizes that HIF1± is important in controlling the activation of the NLRP3 inflammasome that occurs in the infection of macrophages by L. amazonensis. The function of HIF1± during Leishmania infection presents opposing results in the literature, being demonstrated as a factor induced by the parasite that increases disease progression and susceptibility and, on the other hand, as a protective factor. Therefore, this study will allow new access to this question and to understand the molecular basis of NLRP3 inflammasome activation in the Leishmania-macrophage interaction. The findings will be important to advance the knowledge of the immune response of cutaneous leishmaniasis, whose lesions present characteristics of hypoxia.

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