Parasite-mediated nuclear factor kappaB 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 kappaB (NFkappaB) to the nucleus and consequent enhanced expression of interleukin 2 and the interleukin 2 receptor. How T. parva induces persistent NFkappaB activation, required for T cell activation and proliferation, is unknown. We hypothesized that the parasite induces degradation of the IkappaB molecules which normally sequester NFkappaB 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 IkappaBalpha. However, IkappaBalpha reaccumulated to high levels in parasitized cells, which indicated that T. parva did not alter the normal NFkappaB-mediated positive feedback loop which restores cytoplasmic IkappaBalpha. In contrast, T. parva mediated continuous degradation of IkappaBbeta resulting in persistently low cytoplasmic IkappaBbeta levels. Normal IkappaBbeta levels were only restored following T. parva killing, indicating that viable parasites are required for IkappaBbeta degradation. Treatment of T. parva-infected cells with pyrrolidine dithiocarbamate, a metal chelator, blocked both IkappaB degradation and consequent enhanced expression of NFkappaB dependent genes. However treatment using the antioxidant N-acetylcysteine had no effect on either IkappaB levels or NFkappaB activation, indicating that the parasite subverts the normal IkappaB 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.
Palmer
G H
GH
Institute of Animal Pathology, University of Bern, Bern 3012, Switzerland.
Machado
J
J
Fernandez
P
P
Heussler
V
V
Perinat
T
T
Dobbelaere
D A
DA
D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000469:parasitology* / Q000473:pathology; D016328:NF-kappa B / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000469:parasitology* / Q000473:pathology; D016797:Theileria parva; D013801:Theileriasis / Q000276:immunology*
D016328:NF-kappa B