Study activation of inflammasome by toxins isolated from Bothrops venom and modulation of immune response

Abstract

The Bothrops are responsible for about 80 % of reported accidents in Brazil. Bothrops poisoning are described in several places and among these effects is the tissue damage that can result in dysfunction of the affected organ. Two toxins, jararhagin (JAR) and bothropstoxin - I (BthTX - I), isolated from Bothrops jararaca and Bothrops jararacussu, respectively, are involved in intense inflammatory response and tissue damage observed, but they have distinct mechanisms of action. The resolution of tissue injury involves the interaction between mechanisms of tissue repair and immune system. However, the molecular mechanisms by which the innate immune system detects components of the venom and initiates the inflammatory response remain in the study. The inflammatory response is initiated by the detection of signs of acute tissue damage due to disorders of homeostasis or not resulting from microbial agents (damps) and / or recognition of pathogen -associated molecular patterns (PAMPs). Several receptors are involved in the recognition of PAMPs such as the transmembrane and damps represented by the Toll like, and cytosolic protein complexes comprising forming the inflamassomas. NALP3, and NRLC4 Naip5 are examples of the inflammasome that activate their ligands interact with caspase -1 which controls the production of pro- inflammatory cytokines such as IL- 1² and IL-18 piroptose and cell death. Whereas JAR - BthTX and I had relevant proinflammatory inducing in vivo high secretion of IL - 1² and IL - 6 action and also inflamassomas that can be activated by various biological agents and thus promote inflammation, we propose in this project to study the role of inflamassomas in response to these toxins. To do so, we intend to evaluate the activation of caspase- 1 in macrophage cultures incubated with toxins as well as secretion of IL- 1², IL- 6, IL -18, IFN- ³ and nitric oxide (NO). We also intend to study the role of ASC, NALP3 or NRLC4 using wild-type mice (WT) and deficient in these components. In vivo model, we propose to study the inflammatory response generated by the toxins in mice deficient in caspase - 1 or ASC. This project we seek to add relevant information concerning the action of toxins on the immune system and the participation of inflamassomas this process (AU)