Evaluation of the Role of Gasdermin-D Cleavage in Leishmania infantum Infection and Its Impact on the Progression of Visceral Leishmaniasis

• Grant number: 25/13412-2
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2025
• End date: October 31, 2028
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Dario Simões Zamboni
• Grantee: Juliana Cristina Costa Madeira
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 24/16091-0 - Innate Immune Mechanisms Mediated by Cytoplasmic Receptors in the Recognition and Control of Intracellular Pathogen Infections, AP.TEM

Abstract

Leishmaniases comprise a complex of infectious diseases caused by protozoan parasites of the genus Leishmania, affecting millions of people worldwide. Among them, visceral leishmaniasis (VL) is the most severe form of the disease and can be fatal if left untreated. The host immune response plays a pivotal role in controlling the infection, and pyroptosis, an inflammatory form of programmed cell death mediated by gasdermin-D (GSDMD), has emerged as a key process in this context. Canonically, GSDMD is activated by caspase-dependent proteolytic cleavage, leading to the formation of membrane pores and the release of pro-inflammatory cytokines. However, studies from our group suggest that Leishmania parasites may induce non-canonical cleavage of GSDMD through alternative proteases, generating fragments with distinct functional properties and potential implications for inflammatory modulation. This project aims to investigate the mechanisms of alternative GSDMD cleavage during infection with Leishmania infantum, identify the protease(s) involved, and evaluate the functional consequences of this modulation on the inflammatory response and infection control. Cellular and murine models, including Nos2-/- mice as a proposed symptomatic model of VL, will be employed. Clinical samples from patients will also be analyzed to assess inflammasome activation and its association with clinical parameters of the disease. We expect that the results will reveal novel immune evasion mechanisms exploited by Leishmania, providing new insights into host-pathogen interactions and paving the way for the development of more effective therapeutic interventions. (AU)