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Identification of proteins involved in the assembly and activation of the NLRC4 inflammasome in response to Leishmania (L) amazonensis infection

Grant number: 15/24640-4
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): March 01, 2016
Effective date (End): February 28, 2019
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Dario Simões Zamboni
Grantee:Alexandre Luiz Neves Silva
Home 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

Leishmaniasis is a group of diseases caused by protozoa of Leishmania genus. These parasites exhibit a remarkable capacity to survive and proliferate within the phagolysosome of host macrophages. Macrophages are critical for effective and protective immune responses to different diseases, including Leishmaniasis. Macrophages express different pattern recognition receptors (PRR) responsible for recognition of molecular patterns associated with microbes (PAMPs). NLRs are a group of intracellular receptors that recognize endogenous and exogenous danger signals. Some members of this family participate of the inflammasome formation. The inflammasome is able to activate inflammatory caspases, such as caspase-1 that is responsible for processing and secretetion of IL-1² and IL-18, as well to induce an inflammatory form of cell death called pyroptosis. While many publications emphasize the importance of TLRs in the susceptibility and control of Leishmania infection, the role of NLRs is still unclear. We have recently demonstrated that the NLRP3 inflammasome is activated in response to L. amazonensis infection in a process that is required for restriction of parasite infection (Lima-Junior et al, 2013). However, the molecules involved in the activation of NLRP3 in response to L. amazonensis infection are unknown. Recently we found that NLRC4 is activated in response to L. amazonensis infection and plays an important role in controlling infection in macrophages and in vivo. We suggest that NLRC4 is involved in the activation of the NLRP3 inflammasome in response to Leishmania infection, inducing pore formation and potassium efflux. Thus, the aim of this work is to identify molecules involved in NLRC4 inflammasome activation in response to infection by L. amazonensis.