Host and parasite-derived IKK activities direct distinct temporal phases of NF-κB activation and target gene expression following Toxoplasma gondii infection

Activation of NF-kappa B by the intracellular pathogen Toxoplasma gondii is associated with the localization of phosphorylated I kappa B alpha to the parasitophorous vacuole membrane (PVM). This is mediated by a parasite-derived I kappa B kinase (TgIKK) activity and is independent of host IKK function. In the present study, we examined the roles of host IKK and parasite-derived TgIKK on the temporal modulation of NF-kappa B activation. Despite the presence of TgIKK activity at the PVM, nuclear translocation of NF-kappa B and subsequent gene expression exhibited a requirement for the host IKK complex. A detailed kinetic analysis of NF-kappa B activation revealed a biphasic, hierarchical and temporally regulated response. We propose a novel paradigm for the modulation of NF-kappa B-dependent gene expression by T gondii that involves both the host IKK complex and TgIKK activity at different phases of infection. Thus, T gondii effectively alters gene expression in a temporal dimension by exploiting the NF-kappa B signaling machinery and subsequently rewiring the activation circuits of the infected host cell.