Interference by the intracellular parasite Theileria parva with T-cell signal transduction pathways induces transformation and protection against apoptosis.

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.