INVESTIGATING THE ROLE OF INFLAMMASOME ACTIVATION IN THE CONTROL OF T. GONDII

Toxoplasma gondii is one of the most successful pathogens, with an estimated two billion people chronically infected worldwide. A key to the parasite's success at developing a life-long chronic infection is its ability to regulate the host' immune response, including inflammation. An important inflammatory pathway the parasite may be activating is the inflammasome, expressed in macrophages and dendritic cells. Several important human pathogens have been found to act on this pathway, which leads to the secretion of several pro-inflammatory cytokines and caspase-1. Inflammasome activation has been linked to a programmed form of cell death, pyroptosis. Particular intracellular pathogens have been found to inhibit this pathway, preventing host cell death and ensuring pathogen survival, while others activate the inflammasome, potentially using cell death as a method for dissemination. Reports have implicated activation of the Nlrp1 inflammasome in humans with control of parasitic infection. We have found that Toxoplasma activates the inflammasome in mouse and rat macrophages and induces host cell death. The goal of this application is to elucidate the pathway through which Toxoplasma is activating the inflammasome and determine if the activation of host cell death is responsible for the control or dissemination of the parasit, using immunological, biochemical and cell biological techniques.