Subversion of inflammasome functions by Coxiella burnetii

• Grant number: 12/14456-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): November 01, 2012
• Effective date (End): May 31, 2014
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Dario Simões Zamboni
• Grantee: Larissa Dias da Cunha
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The intracellular receptors Nod-like (NLRs) play a pivotal role in the recognition of pathogens and infection control, sensing molecular pathogenic signatures within the cytosol of the host cell. NLRs receptors can induce the activation of the inflammasome, a molecular scaffold triggering caspase-1 activation, culminating into cellular responses as secretion of cytokines, unconventional secretion of proteins, pyroptosis and infection control. On the other hand, expression of bacterial delivery systems and the secretion of effectors within the cytosol are important strategies in the subversion of host cell functions and recognition systems by pathogens. During her PhD, the candidate showed that Coxiella burnetii, a highly subversive intracellular pathogen, inhibits the activation of caspase-11-dependent inflammasome responses such as caspase-1 cleavage, activation of IL-1² and IL-1± and pore formation in the host cell membrane in response to pathogens as Legionella pneumophila and Escherichia coli. Additionally, we identified the protein IcaA of C. burnetii as the effector responsible for the inflammasome subversion. IcaA is secreted by a type IV Dot/Icm secretion system of L. pneumophila, homologue to that of C. burnetii, and promotes inhibition of inflammasome activation induced by caspase-11 in response to the pathogen. Herein, we propose the following aims: 1) to determine the molecular mechanisms of caspase-11-dependent inflammasome inhibition by IcaA, and evaluate its role for C. burnetii pathogenesis; 2) to identify the molecular mechanisms and additional effectors involved in inflammasome subversion by C. burnetii; 3) to evaluate the contribution of the inflammasome in infection control by macrophages.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CERQUEIRA, DAIANE M.; PEREIRA, MARCELO S. F.; SILVA, ALEXANDRE L. N.; CUNHA, LARISSA D.; ZAMBONI, DARIO S.. Caspase-1 but Not Caspase-11 Is Required for NLRC4-Mediated Pyroptosis and Restriction of Infection by Flagellated Legionella Species in Mouse Macrophages and In Vivo. JOURNAL OF IMMUNOLOGY, v. 195, n. 5, p. 2303-2311, SEP 1 2015. (12/14456-3, 11/22617-4, 13/08216-2, 14/04684-4, 12/15932-3, 12/16941-6)