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Temporal and transcriptional inflammasomes regulation in Legionella pneumophila recognition by macrophages

Grant number: 12/16941-6
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): January 01, 2013
Effective date (End): January 31, 2014
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Dario Simões Zamboni
Grantee:Daiane Maria Cerqueira
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


Legionella pneumophila is a Gram-negative bacterium responsible to cause, in humans, a severe pneumonia called Legionnaires' disease. Inflammasomes are multiprotein cytoplasmic complexes that act as pathogen (PAMPs) and damage associated molecular patterns (DAMPs). The restriction of L. pneumophila is dependent on NLRC4/Naip5 inflammasome, which recognizes bacterium flagellin, culminating in caspase-1 activation, pyroptosis and infection control. In addition, caspase-1 induces ASC-dependent IL-1² secretion. Recent data produced in the laboratory demonstrated the existence of a caspase-11 dependent inflammasome, which is activated when LPS-primed macrophages are infected with L. pneumophila deficient in flagellin (flaA). This process induces ASC-dependent caspase-1 activation and cleavage. Recently, it has been described a caspase-11 activation model mediated by TLR4/TRIF/IFN type I, which shows that caspase-11 activation is transcriptionally regulated. This pathway activation was demonstrated in response to diverse Gram-negative bacteria, however, L. pneumophila does not activate this pathway because its LPS fail to trigger TLR4 activation. Collectively, these data support the existence of, at least, two pathways activated by L. pneumophila that triggers caspase-1 activation and cleavage. Nevertheless, little is known regarding temporal activation of inflammasomes, as well as their temporal and transcriptional regulation. Thereby, the aim of this project is to investigate the inflammasomes temporal and transcriptional regulation in response to L. pneumophila infection. In addition, possible receptors and intracellular pathways leading to caspase-11 expression in response to this pathogen will be investigated.

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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, . (12/14456-3, 11/22617-4, 13/08216-2, 14/04684-4, 12/15932-3, 12/16941-6)

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