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.
Toxoplasma gondii is an obligate intracellular parasite capable of infecting all warm-blooded animals, including humans. The parasite causes serious disease in immunocompromised individuals and developing fetuses. A detailed understanding of the mechanism through which this parasite is able to modulate the host immune response will lead us to new parasite-specific therapies.
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