Determination of the cell death role in leukocyte recruitment and control of Legionella pneumophila infection

• Grant number: 19/21420-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: October 01, 2020
• End date: September 30, 2022
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Dario Simões Zamboni
• Grantee: Marco Antonio Ataide Silva
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 14/04684-4 - The inflammasome in the host response against intracellular pathogens and the microbial mechanisms for its evasion, AP.TEM

Abstract

The inflammasome is a molecular platform found in the cytoplasm of eukaryotic cells, which activation leads to the processing of caspase-1 and cleavage of IL-1b and IL-18 into their active forms, as well as induction of inflammatory cell death through gasdermin-D activation. The receptor NLRC4, an essential cytosolic sensor for the activation of Naip/NLRC4 inflammasome is triggered by bacterial flagellin. This pathway is critical for the efficient control of flagellated bacterial infection, such as Legionella pneumophila. The restriction of bacterial proliferation is mediated by cell death induction, being independent on cytokine release. It has shown that Caspase-1-deficient macrophages present delayed cell death during L. pneumophila infection. This event is mediated by the adaptor ASC and the effector Casp8 which are also important for restriction of infection. The search for the downstream factors demonstrated that both Casp1 and Casp8 are involved in Caspase-7 cleavage, which is the effector that restricts L. pneumophila infection in vitro. In this sense, the double deficiency of both Casp7 and GsdmD culminates in increased susceptibility of macrophages and mice to bacterial replication. However, the mechanisms involved in this setting are not known, being the main objective of this study. The hypothesis is that cell death mediated by Casp7 and GsdmD is responsible for restriction of bacterial proliferation by triggering efficient cell recruitment to the infected lungs during L. pneumophila infection. The data obtained should identify some mechanisms associated to the bacterial control during lung infections and inflammatory conditions. This new knowledge would also be important for the development of new strategies to intervene acute pneumonia caused by bacterial infections. (AU)