Cross talk between RIP3K and NLRP3 during T. cruzi infection

Abstract

The intracellular protozoan Trypanosoma cruzi is the causative agent of Chagas disease, a serious and chronic pathology that affects millions of people worldwide. It is known that control of T. cruzi infection requires the actions of multiple mechanisms of innate immunity that are triggered by pattern recognition receptors (PRRs). Recently, our group demonstrated the involvement of NLRP3 and caspase-1 in the control of T. cruzi infection. Mice NLRP3 - / - and caspase-1 - / - presented high parasitemias and their macrophages were not able to produce nitric oxide and control the infection, different from what was observed in wild mice. In addition to the microbicidal mechanisms induced by PRRs, necroptosis, a type of cell death regulated with phenotype similar to necrosis, has been identified as an important mechanism in the control of several pathogens infections. Studies have shown that in the absence of molecules essential for necroptosis, such as RIPK3, animals become more susceptible to various types of infection, such as viral and bacterial infections. In addition to inducing death by necroptosis, RIPK3 is also involved in the activation of inflammatory responses, including those mediated by the inflammasome NLRP3. Thus, it is possible that RIPK3 and NLRP3 collaborate to modulate the activation of inflammasomes, as well as for the secretion of inflammatory cytokines in a noncanonical way, necessary for the control of certain infections. Surprisingly, there is, to date, no work investigating the role of necroptosis in the control of T. cruzi infection nor on the role of RIPK3 in the activation of NLRP3 inflammation in response to infection by this parasite. Thus, the central proposal of this project is to investigate the role of RIPK3 in both the induction of the necroptosis pathway and in the regulation of inflammatory activation and its impact on the control of T. cruzi infection. (AU)