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Identification of Caspase-7 substrates operating in the inflammasome pathway for the control of Legionella pneumophila infection

Grant number: 23/09371-3
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): December 01, 2023
Effective date (End): March 31, 2027
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Dario Simões Zamboni
Grantee:Amanda de Matos Becerra
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


The NLRC4 inflammasome is a multiprotein platform involved in the activation of caspases effects from the recognition of different microbes in the cytosol. After the recognition of bacterial flagellin, NAIP5/NLRC4 lead to activation of caspase-1 (CASP1) and caspase-7 (CASP7), promoting host resistance to infection through a deathprogrammed cell known as pyroptosis.Legionella pneumophila is known to activate the NAIP5/NLRC4 inflammasome, thus being a well-established experimental model for studying this pathway. Work published by our laboratory showed that in the absence of CASP1, caspase-8 (CASP8) can also promote CASP7 activation triggering a pyroptotic cell death, which is important for bacterial control. Besides it was observed that mice deficient for Gsdmd/Casp7 have a high susceptibility as well as Nlrc4-/-, indicating that these molecules can act in a redundant but independent in controlling L. pneumophila replication. these evidences reveal that the recognition system of intracellular bacteria is highly specialized, presenting several ways to control the infection based on conserved patterns. Studies have shown that this replication control occurs mainly through mechanism of pyroptosis, with the formation of pores in the plasma membrane and cell death, eliminating the intracellular replicative niche. However, the mechanism by which CASP7 induces formation of these pores with subsequent cell death and replication control, in a way independent of GSDMD, it is not yet clear. Thus, the aim of this project is to identify new molecules that are activated by CASP7 during L. pneumophila infection and evaluate their mechanisms of action. This study should reveal new mechanisms responsible for the control of infection not only by L. pneumophila, but by several pathogens intracellular pathways controlled by inflammasomes.

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