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The role of the ESCRT machinery in membrane repair and cell death during Leishmania spp. infection

Grant number: 19/15323-6
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): October 01, 2019
Effective date (End): September 30, 2020
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Dario Simões Zamboni
Grantee:Renan Villanova Homem de Carvalho
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Leishmania spp. are the causative agents of Leishmaniasis, a disease that affects millions of people worldwide. Several studies have demonstrated that these parasites may engage Pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs) and Nod-like receptors (NLRs). In the latter case, activation of the NLRP3 inflammasome by Leishmania spp. has been demonstrated by many groups, being critical for the development of the disease. However, the mechanisms regulating its assembly are still largeIy unknown. NLRP3 activation may result in cytokine processing, inflammation, and, ultimately, in an inflammatory form of cell death named pyroptosis. Despite the vast literature demonstrating pyroptotic cell death upon bacterial infections, whether Leishmania induces massive cell death remains elusive. Therefore, this project aims to investigate the mechanisms regulating pyroptosis in the context of Leishmania infection. Initially, we performed infections in bone marrow-derived macrophages (BMDMs) with Leishmania amazonensis parasites and found that despite inducing cytokine processing via the NLRP3 inflammasome, cell death is poorly induced by these parasites compared to a gram-negative bacteria, Legionella pneumophila. Thus, my visit to the laboratory of Dr. Petr Broz aims to elucidate the molecular pathways triggered by L. amazonensis responsible for membrane repair and inhibition of cell death. Our idea is to investigate the role of ESCRT proteins in membrane repair and cytokine release, which was recently demonstrated as an important regulatory mechanism against pyroptosis. The elucidation of the pathways triggered by Leishmania will help to better understand host-pathogen interaction during infection, and interfering with pyroptotic cell death could become a promising target for parasite elimination and control of the disease.