Initiation and termination of NF-κB signaling by the intracellular protozoan parasite Toxoplasma gondii

Signaling via the NF-kappa B cascade is critical for innate recognition of microbial products and immunity to infection. As a consequence, this pathway represents a strong selective pressure on infectious agents and many parasitic, bacterial and viral pathogens have evolved ways to subvert NF-kappa B signaling to promote their survival. Although the mechanisms utilized by microorganisms to modulate NF-kappa B signaling are diverse, a common theme is targeting of the steps that lead to I kappa B degradation, a major regulatory checkpoint of this pathway. The data presented here demonstrate that infection of mammalian cells with Toxoplasma gondii results in the activation of IKK and degradation of I kappa B. However, despite initiation of these hallmarks of NF-kappa B signaling, neither nuclear accumulation of NF-kappa B nor NF-kappa B-driven gene expression is observed in infected cells. However, this defect was not due to a parasite-mediated block in nuclear import, as general nuclear import and constitutive nuclear-cytoplasmic shuttling of NF-kappa B remain intact in infected cells. Rather, in T gondii-infected cells, the termination of NF-kappa B signaling is associated with reduced phosphorylation of p65/ReIA, an event involved in the ability of NF-kappa B to translocate to the nucleus and bind DNA. Thus, these studies demonstrate for the first time that the phosphorylation of p65/ReIA represents an event downstream of I kappa B degradation that may be targeted by pathogens to subvert NF-kappa B signaling.