Evaluation of the role of neutrophil extracellular traps in the pathogenesis and control of pulmonary replication of Legionella spp.

• Grant number: 24/13944-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: December 01, 2024
• End date: February 29, 2028
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Dario Simões Zamboni
• Grantee: Rhanoica Oliveira Guerra
• 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

Legionella spp. are Gram-negative bacteria that can infect humans through the inhalation of contaminated aerosols and trigger Legionnaires' Disease, a severe pneumonia that can lead to death. The innate immune system plays a crucial role in the initial recognition of the pathogen. One of the main host defense mechanisms in response to L. pneumophila infection is the activation of inflammasomes, which are multiprotein complexes formed in the cytosol of cells. This results in the release of pro-inflammatory cytokines (IL-1² and IL-18) and pyroptotic cell death mediated by Gasdermin-D (GSDMD). Pyroptosis is responsible for the elimination of the bacterial replicative niche and the formation of cellular debris, known as pore-induced intracellular traps, which are subsequently eliminated by phagocytes. In addition, during pyroptosis, the cell ruptures and releases Damage Associated Molecular Patterns (DAMPs) into the extracellular environment, which can amplify the inflammatory response by recruiting and activating other cells, such as neutrophils. Neutrophils, in addition to their phagocytic capacity and release of lytic enzymes, can form extracellular traps, known as NETs, composed of networks of decondensed DNA complexed with histones and granular proteins. Studies have also shown that other cells of the immune system, such as macrophages, are capable of releasing extracellular traps, called macrophage extracellular traps (METs). Both NETs and METs play crucial roles in capturing and eliminating invading microorganisms. However, no comprehensive investigations have yet been carried out into the occurrence of these extracellular traps during L. pneumophila infection, nor into the signaling pathways and release dynamics of NETs and METs. Studies indicate that pore formation by GSDMD is a key step in the release of NETs, suggesting coordination between the inflammasome pathways and the cell death pathway known as NETosis. In addition, excessive production and inadequate clearance of extracellular traps are involved in the pathophysiology of several lung diseases. In the context of the lung disease caused by L. longbeachae, which is lethal in mice, it is crucial to investigate whether the release of NETs and METs contributes to the pathophysiology of the disease. Understanding the functions and molecular mechanisms of extracellular traps could enable the development of targeted therapies to control their production, offering strategies aimed at treating bacterial lung infections.