Interference by the intracellular parasite Theileria parva with T-cell signal transduction pathways induces transformation and protection against apoptosis.
D. Dobbelaere et al., Interference by the intracellular parasite Theileria parva with T-cell signal transduction pathways induces transformation and protection against apoptosis., VET IMMUNOL, 72(1-2), 1999, pp. 95-100
The intracellular parasite Theileria parva transforms bovine T-lymphocytes,
inducing uncontrolled proliferation. Upon infection, cells cease to requir
e antigenic stimulation and exogenous growth factors to proliferate. Earlie
r studies have shown that pathways triggered via stimulation of the T-cell
receptor are silent in transformed cells. This is reflected by a lack of ph
osphorylation of key signalling molecules and the fact that proliferation i
s not inhibited by immunosuppressants such as cyclosporin and ascomycin tha
t target calcineurin. This suggests that the parasite bypasses the normal T
-cells activation pathways to induce proliferation. Among the MAP-kinase pa
thways, ERK and p38 are silent, and only Jun N-terminal kinase is activated
. This appears to suffice to induce constitutive activation of the transcri
ption factor AP-1. More recently, it could be shown that the presence of th
e parasite in the host cell cytoplasm also induces constitutive activation
of NF-kappa B, a transcription factor involved in proliferation and protect
ion against apoptosis. Activation is effectuated by parasite-induced degrad
ation of I kappa Bs, the cytoplasmic inhibitors which sequester NF-kappa B
in the cytoplasm. NF-kappa B activation is resistant to the antioxidant N-a
cetyl cysteine and a range of other reagents, suggesting that activation mi
ght occur in an unorthodox manner. Studies using inhibitors and dominant ne
gative mutants demonstrate that the parasite activates a NF-kappa B-depende
nt anti-apoptotic mechanism that protects the transformed cell form spontan
eous apoptosis and is essential for maintaining the transformed state of th
e parasitised cell. (C) 1999 Elsevier Science B.V. All rights reserved.