Toxoplasma gondii is an obligate intracellular parasite that can cause serious disease in immune-suppressed patients and fetuses and vision loss in otherwise healthy individuals. Activation of host innate immunity is crucial for early detection of Toxoplasma but an over-activation of innate immune responses can also lead to pathological inflammation. During the previous funding period we have determined that activation of the inflammasome upon detection of Toxoplasma infection is an important innate immune defense mechanism. In this renewal application we will identify the molecular mechanisms by which Toxoplasma activates the inflammasome and the NF?B transcription factor, which is important for activating innate immunity. Inflammasomes are multiprotein complexes that participate in the production of interleukin (IL)-1 and IL-18, which are cytokines that play important roles in the immune response to many pathogens, including Toxoplasma. Inflammasome activation can also induce a form of rapid cell death known as pyroptosis, which can remove the niche that intracellular pathogens need for replication. There are two signals involved in the secretion of active IL-1: 1) the activation of the transcription factor NF?B, which leads to the expression o pro-IL-1 and 2) the detection of microbial and environmental danger signals by cytosolic receptors (named NLRs) leading to their multimerization along with pro-caspase-1 (together called the inflammasome). Pro-caspase-1 is auto catalytically processed when the inflammasome is assembled and can induce pyroptosis but also cleave pro-IL-1 and pro-IL-18 leading to their subsequent secretion. To co-opt the host cell, Toxoplasma secretes effector molecules named ROPs and GRAs from its rhoptry and dense granule organelles, respectively. We have determined that Toxoplasma GRA15 can activate the NFkB pathway and thereby provide signal 1. We have also shown that Toxoplasma activates the Lewis rat NLRP1-inflammasome, which leads to pyroptosis and inhibition of Toxoplasma growth. Besides Anthrax lethal toxin, Toxoplasma is the only known other activator of the NLRP1-inflammasome. It is therefore important to identify the host and parasite proteins that determine Toxoplasma-inflammasome interactions. In our first aim we will determine the exact mechanism by which Toxoplasma GRA15 modulates the NF?B transcription factor. In our second aim we will focus on identifying the parasite molecules involved in inflammasome activation by Toxoplasma. These innate immune responses play a role in determining human susceptibility to toxoplasmosis, and are important for defense against numerous other pathogens. Results from this research should lead to a better understanding of Toxoplasma-innate immune system interactions and will provide novel insights into NLRP1 activation in general. This will help the development of improved treatments against toxoplasmosis and other pathogenic diseases.
Toxoplasma gondii is an obligate intracellular pathogen that can cause serious disease in immune-suppressed people, such as AIDS patients, and fetuses and is also a major cause of blindness in otherwise healthy people. We are studying Toxoplasma-innate immune system interactions that determine early parasite control and activation of the adaptive immune system and are therefore critical in determining host survival. A better understanding of Toxoplasma-innate immune system interactions is needed and will help the development of improved treatments against toxoplasmosis and other pathogenic diseases.
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