Identification of toxoplasma gondii genes involved in the strain-specific modulation of IL-12 cytokine secretion

Abstract

Toxoplasma gondii is an intracellular pathogen that causes life-threatening toxoplasmosis in developing fetuses and immune-compromised individuals. An immune response to a Toxoplasma infection is characterized by the stimulation of high levels of interleukin- 12 (IL- 12), followed by the production of interferon-y (IFN-y) by immune cells. Although IFN-y is the main mediator of resistance to Toxoplasma infection, Toxoplasma is able to manipulate the immune response through the regulation of IL- 12 production. Toxoplasma has been shown to modulate the induction of IL-12 in a strain-specific manner. An infection with a type II strain, but not type I and III strains, induce high levels of IL- 12 production by macrophages in vitro. Previous studies have implicated two Toxoplasma genes that play a role in this strainspecific difference in IL- 12 production. A rhoptry protein kinase, ROP 16, from type I and III strains, was found to be crucial in the suppression of IL-12. A type II dense granule protein, GRA 15, induces IL-12 through NF-KB activation. I have screened F1 progeny from a type III x type II cross for IL-12 induction and NF-KB activation. My preliminary experiments indicate that there are other Toxoplasma factors involved in the strain-specific inhibition of IL-12, and this inhibition has a genetic basis. To understand the role of IL-12 regulation by Toxoplasma, I intend to (i) identify novel Toxoplasma genes involved in the inhibition of IL- 12 secretion (ii) test and characterize the effects of the Toxoplasma protein ROP38 on IL-12 signaling and (iii) determine the target/s of Toxoplasma inhibition of IL-12 production.