1. ¹Laboratoire de Signalisation Immunoparasitaire, CNRS URA CNRS 2581, Département de Parasitologie, Institut Pasteur, Batiment Elie Metchnikoff, 25-28 rue du Dr Roux, 75724 Paris Cedex 15, France
2. ²Department of Stomatology, University of California, San Francisco, 513 Parnassus Ave., HSW 604, San Francisco, CA 94143-0512, USA
3. ³The Royal Veterinary College, Hawkshead Lane, North Mymms, Hertfordshire AL9 7TA, UK

Correspondence: G Langsly, E-mail: langsley@pasteur.fr

Received 8 June 2004; Revised 1 October 2004; Accepted 21 October 2004; Published online 6 December 2004.

Abstract

Theileria parasites infect and transform bovine lymphocytes, but host cell immortalization is reversible, as upon parasite death the lymphocytes rapidly die of apoptosis. Infection leads to a marked augmentation in the levels of lymphocyte c-Myc, and the parasite achieves this by inducing increased c-myc transcription and by prolonging the half-life of the transcription factor. Reduction in c-Myc turnover can be ascribed to CK2-mediated phosphorylation of the transcription factor. A parasite-dependent GM-CSF autocrine loop activates a JAK2/STAT3 signalling pathway that contributes to heightened c-myc transcription, and inhibition of the pathway leads to caspase 9 activation and apoptosis that can be directly ascribed to a reduction in c-Myc. An antiapoptotic role for c-Myc was clearly demonstrated by specific inhibition of c-myc expression with antisense oligonucleotides, and this correlates with loss of the antiapoptotic protein Mcl-1, and, consistently, ectopic expression of c-Myc abrogates B-cell death induced upon JAK2 inhibition. Thus, Theileria parasites ensure the survival of their host lymphocytes via specific activation of c-Myc.