Role of inflammasomes and IL-1 in experimental infection by Trypanosoma cruzi

• Grant number: 13/00579-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2013
• End date: July 03, 2017
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: João Santana da Silva
• Grantee: Grace Kelly da Silva
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID
• Associated scholarship(s): 14/25585-4 - Mechanisms that regulate the processing of IL-1a, IL-1b and their role during experimental Trypanosoma cruzi infection, BE.EP.PD

Abstract

The innate immune response against Trypanosoma cruzi (causative agent of Chagas disease) comprises several pattern recognition receptors (PRRs), including the family Toll Like Receptors (TLRs) and intracellular receptor Nod1. However, we observed a cytokine production in response to T. cruzi independent of TLRs and Nod1 receptor, suggesting that there are additional components in the innate immune response against this parasite. In this context, the NLRs that activate the inflammasomes are candidate receptors that deserve renewed investigation. The NLRs, family of intracellular receptors that sense pathogen-associated molecular patterns (PAMPs), include NLRP3, NLRP6, NLRC4 and, potentially, the NLRP12. These NLRs interact with an adapter molecule termed ASC, culminating in the activation of caspase-1. The scaffold formed by a receptor, caspase-1 and ASC is named inflammasome, which is essential to induce the production of active IL-1² and IL-18. Besides the NLRs, the AIM2 cytoplasmic receptor recognizes the viral or bacterial DNA, associated with ASC and activates caspase-1 also forming one inflammasome. Recently, we have shown that ASC inflammasome is required for activation of caspase-1, induction of IL-1², and resistance to infection by Trypanosoma cruzi. However, it was not possible to identify the intracellular receptors responsible for trigger of this signalling pathway in response to this parasite. Moreover, we didn't find the mechanisms modulated by IL-1 during this infection. Therefore, the aim of this project is to identify the receptors that activate caspase-1 dependent of inflammasome ASC and understand the role of IL-1 in the immune response against T. cruzi.