Journal article
Parasite-mediated nuclear factor κB regulation in lymphoproliferation caused by Theileria parva infection
Proceedings of the National Academy of Sciences - PNAS, Vol.94(23), pp.12527-12532
11/11/1997
Handle:
https://hdl.handle.net/2376/116804
PMCID: PMC25026
PMID: 9356483
Abstract
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 κB (NFκB) to the nucleus and consequent enhanced expression of interleukin 2 and the interleukin 2 receptor. How
T. parva
induces persistent NFκB activation, required for T cell activation and proliferation, is unknown. We hypothesized that the parasite induces degradation of the IκB molecules which normally sequester NFκB 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 IκBα. However, IκBα reaccumulated to high levels in parasitized cells, which indicated that
T. parva
did not alter the normal NFκB-mediated positive feedback loop which restores cytoplasmic IκBα. In contrast,
T. parva
mediated continuous degradation of IκBβ resulting in persistently low cytoplasmic IκBβ levels. Normal IκBβ levels were only restored following
T. parva
killing, indicating that viable parasites are required for IκBβ degradation. Treatment of
T. parva
-infected cells with pyrrolidine dithiocarbamate, a metal chelator, blocked both IκB degradation and consequent enhanced expression of NFκB dependent genes. However treatment using the antioxidant
N-
acetylcysteine had no effect on either IκB levels or NFκB activation, indicating that the parasite subverts the normal IκB 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.
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Details
- Title
- Parasite-mediated nuclear factor κB regulation in lymphoproliferation caused by Theileria parva infection
- Creators
- Guy H Palmer - Institute of Animal Pathology, University of Bern, Bern 3012, Switzerland; andJoel Machado - Institute of Animal Pathology, University of Bern, Bern 3012, Switzerland; andPaula Fernandez - Institute of Animal Pathology, University of Bern, Bern 3012, Switzerland; andVolker Heussler - Institute of Animal Pathology, University of Bern, Bern 3012, Switzerland; andTherese Perinat - Institute of Animal Pathology, University of Bern, Bern 3012, Switzerland; andDirk A. E Dobbelaere - Institute of Animal Pathology, University of Bern, Bern 3012, Switzerland; and
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.94(23), pp.12527-12532
- Publisher
- The National Academy of Sciences of the USA
- Identifiers
- 99900547856501842
- Language
- English
- Resource Type
- Journal article