Modulation of host NF-[k̳̳a̳p̳p̳a̳]B pathway by the Toxoplasma gondii secreted factor, GRA15

Abstract

The apicomplexan protozoan Toxoplasma gondii is an obligate intracellular pathogen that infects all warm blooded animals, including nearly thirty percent of the human population worldwide. Toxoplasma's success as a parasite owes largely to its ability to commandeer its host's immunologic and metabolic processes for its own benefit. During infection, Toxoplasma secretes a large number of proteins into the host cell. Many of these parasite factors modulate the signaling pathways of the host, including the pathway toward NF-[kappa]B activation. The NF-[kappa]B response to infection regulates the direction of host immunity, toward either the classical inflammatory or the alternative non-inflammatory pathway. Using forward genetic analysis, we have isolated the secreted protein GRA 15 that is necessary and sufficient for host NF-[kappa]B activation. We find that GRA 15 activates NF-[kappa]B nuclear translocation and transcriptional regulation in an IKK- and TRAF6-dependent manner. We additionally show that GRA 15 may complex with TRAF3. Some Toxoplasma strains activate the host NF-[kappa]B pathway much more than others. A combination of factors, including differences in expression and sequence of GRA 15, as well as other inhibitory parasite factors are responsible for conferring these strain differences.