Modulation of innate immune signaling pathways by the intracellular pathogen Toxoplasma gondii

Abstract

Toxoplasma gondii, an obligate intracellular protozoan parasite, is one of the most successful eukaryotic pathogens. It can infect virtually any warm-blooded animal, including humans, in whom it can cause serious disease. Its success is likely due to its ability to modulate host immune responses and host innate immune signaling pathways allowing it to establish a chronic infection with few symptoms in its hosts, which favors transmission to new hosts. Here, we report that Toxoplasma activates NF-[kappa]B and inhibits STAT1 signaling pathways to promote both its own survival and the survival of its host. We identified GRA15, a novel Toxoplasma secreted factor that activates the host cell NF-[kappa]B pathway. GRA15 is polymorphic between Toxoplasma strains and only active in the type II clonal lineage. GRA15 expression increases host pro-inflammatory cytokine production in vivo, thereby helping the host to control parasite growth. Conversely, Toxoplasma infection dampens the activation of other immune responses by inhibiting IFN-[gamma] and STAT1 signaling. All of the Toxoplasma strains that we have tested directly inhibit the activity of STAT1, the transcription factor through which IFN-[gamma] signals. We found that infection does not inhibit STAT1 phosphorylation, dimerization, nuclear translocation, or DNA binding. Instead, Toxoplasma must act even farther downstream, perhaps by inhibiting the recruitment of co-activators or RNA polymerase. Infection actually increased the association of STAT1 with DNA, which has been shown previously to be associated with decreased STAT1 transcriptional activity. The Toxoplasma effector that inhibits STAT1 remains unknown, but our results suggest that it is not secreted into the host cell upon invasion but must interface with its cellular target after the parasitophorous vacuole is formed. A deeper knowledge of how and why Toxoplasma modulates these processes will help us to understand more about the basic signaling pathways themselves and to discover clues on how to better treat Toxoplasma infections in humans.