Activation of NLRP3 inflamasome during infection by Paracoccidioides brasiliensis

• Grant number: 12/08112-0
• Support Opportunities: Scholarships in Brazil - Master
• Data de Início da vigência: July 01, 2012
• Data de Término da vigência: January 31, 2014
• Área de conhecimento: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: João Santana da Silva
• Grantee: Natália Ketelut Carneiro
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Paracoccidioidomycosis (PCM) is a chronic systemic disease with granulomatous alterations, caused by Paracoccidioides brasiliensis. The host defense to pulmonary infection is mediated by the secretion of several antimicrobial proteins by lung epithelium and phagocytic activity of resident alveolar macrophages. Signaling pathways of the phagocytic cellular system can be activated by various microbial antigens released into the intracellular environment, which might bind to receptors of pattern recognition. The receptor-type NOD (NLRs), unlike of the Toll like receptors (TLRs), consists of intracellular proteins which are soluble in the cytoplasm. The antigen recognition allows the inflammasome activation, triggering the production of pro-inflammatory cytokines. The Nlrp3 receptor is activated by endogenous and exogenous stimuli followed by connection with the adapter molecule ASC which in turn activates caspase-1. This molecular plataform ensures cleavage of inactive forms of pro-IL-1² and pro-IL-18 in pro-inflammatory cytokines IL-1² and IL-18, which activate neutrophils and macrophages to phagocyte invading pathogens and release toxic oxygen radicals and nitrogen, which are essential for the clearance of the pathogenic microorganisms. Until now, has not been elucidated the involvement of Nlrp3 inflammassome during experimental PCM. Previous results demonstrate that infection by P. brasiliensis induces the production of IL-1² and the deficiency of caspase-1 or ASC confers susceptibility to P. brasiliensis during the experimental infection. Thus, the main objective of this current project is to evaluate the importance of Nlrp3 receptor signaling in experimental PCM with focus on innate immune response that lead to protective immunity against the Paracoccidioides brasiliensis infection.