Scholarship 14/00447-8 - Imunidade inata, Piroptose - BV FAPESP
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Role of caspase-11 in inflammasome activation and infection control in response to Coxiella burnetii and Legionella pneumophila

Grant number: 14/00447-8
Support Opportunities:Scholarships in Brazil - Master
Start date: May 01, 2014
End date: June 30, 2015
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Dario Simões Zamboni
Grantee:Juliana Magro Ribeiro
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The innate immune response relies on the recognition of molecular patterns (PRRs) receptors to identify the presence of microorganisms and generate an effective response to infection control. Cytoplasmic PRRs, such as those belonging to the family of Nod-like receptors (NLRs), are essential to the recognition of intracellular pathogens. Most NLRs induce activation of caspase-1 by the aggregation of the involved molecules in a molecular platform known as the inflammasome. Activation of the inflammasome culminates in cytokine secretion (IL-1², IL-1±, IL-18), unconventional protein secretion, inflammatory cell death (pyroptosis) and infection control. Recently it was demonstrated that caspase-11 regulates inflammasome activation in response to Gram-Negative bacteria that get access to host cell cytosol.. Caspase-11 induces caspase-1-independent pyroptosis and IL-1± secretion, but also regulates caspase-1 activation and IL-1² mediated by Nlrp3. Legionella pneumophila induces caspase-1 activation by at least two distinct pathways: 1) Nlrc4 and Naip5 trigger caspase-1 activation by recognition of bacterial flagellin and 2) caspase -11 mediates caspase-1 independent pyroptosis and Nlrp3-dependent caspase-1 activation. However, the mechanisms of induction of caspase -11-dependent inflammasome activation by L. pneumophila, are not well understood. Furthermore, the contribution of other receptors to inflammasome activation by L. pneumophila is unknown. Coxiella burnetii is an intracellular pathogen phylogenetically close to L. pneumophila. However, C. burnetii does not lead to inflammasome activation. Our previous investigations revealed that the secreted effector protein encoded by the gene CBU_1823 of C. burnetii inhibits the activation of caspase-11-dependent inflammasome activation. Thus, L. pneumophila and C. burnetii are two important pathogens to understand the cellular mechanisms by which caspase-11 contributes to the control of infection by intracellular pathogens. The objective of this project is to investigate the role of caspase-11 in inflammasome activation and infection control, using Coxiella burnetii and Legionella pneumophila as a model. (AU)

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