Parasite-mediated nuclear factor kappa B regulation in lymphoproliferation caused by Theileria parva infection

Infection of cattle with the protozoan Theileria parva results in uncontrolled T lymphocyte proliferation resulting in lesions resembling multicentric lymphoma. Parasitized cells exhibit autocrine growth characterized by persistent translocation of the transcriptional regulatory factor nuclear factor kappa B (NF kappa B) to the nucleus and consequent enhanced expression of interleukin 2 and the interleukin 2 receptor. How T. parva induces persistent NF kappa B activation, required for T cell activation and proliferation, is unknown, We hypothesized that the parasite induces degradation of the I kappa B molecules which normally sequester NF kappa B in the cytoplasm and that continuous degradation requires viable parasites, Using T. parva-infected T cells, we showed that the parasite mediates continuous phosphorylation and proteolysis of I kappa B alpha, However, I kappa B alpha reaccumulated to high levels in parasitized cells, which indicated that T. parva did not alter the normal NF kappa B-mediated positive feedback loop which restores cytoplasmic I kappa B alpha. In contrast, T. parva mediated continuous degradation of I kappa B beta resulting in persistently low cytoplasmic I kappa B beta levels, Normal I kappa B beta levels were only restored following T, parva killing, indicating that viable parasites are required for I kappa B beta degradation, Treatment of T. parva-infected cells with pyrrolidine dithiocarbamate, a metal chelator, blocked both I kappa B degradation and consequent enhanced expression of NF kappa B dependent genes, However treatment using the antioxidant N-acetylcysteine had no effect on either I kappa B levels or NF kappa B activation, indicating that the parasite subverts the normal I kappa B regulatory pathway downstream of the requirement for reactive oxygen intermediates, Identification of the critical points regulated by T. parva may provide new approaches for disease control as well as increase our understanding of normal T cell function.