Theileria annulata is a tick-transmitted apicomplexan parasite that infects and transforms bovine leukocytes into disseminating tumours that cause a disease called tropical theileriosis. Using comparative transcriptomics we identified genes transcriptionally perturbed during Theileria-induced leukocyte transformation. Dataset comparisons highlighted a small set of genes associated with Theileria-transformed leukocyte dissemination. The roles of Granzyme A (GZMA) and RAS guanyl-releasing protein 1 (RASGRP1) were verified by CRISPR/Cas9-mediated knockdown. Knocking down expression of GZMA and RASGRP1 in attenuated macrophages led to a regain in their dissemination in Rag2/γC mice confirming their role as dissemination suppressors in vivo. We further evaluated the roles of GZMA and RASGRP1 in human B lymphomas by comparing the transcriptome of 934 human cancer cell lines to that of Theileria-transformed bovine host cells. We confirmed dampened dissemination potential of human B lymphomas that overexpress GZMA and RASGRP1. Our results provide evidence that GZMA and RASGRP1 have a novel tumour suppressor function in both T. annulata-infected bovine host leukocytes and in human B lymphomas.
Bibliographical noteKAUST Repository Item: Exported on 2020-11-10
Acknowledged KAUST grant number(s): OSR-2015-CRG4-2610
Acknowledgements: This study was supported by a Competitive Research Grant from the Office for Sponsored Research (OSR-2015-CRG4-2610) at King Abdullah University of Science and Technology (KAUST) awarded to A. P. and G. L. Z. R. acknowledges KAUST for awarding her PhD studentship. S. T. was supported by a post-doctoral fellowship from ParaFrap (ANR-11-LABX-0024) and in addition to ANR-11-LABX-0024, G. L. also acknowledges core support from INSERM and the CNRS. We thank members of the Bioscience Core Laboratory (BCL) at KAUST for producing the raw sequencing datasets. We also thank Franck Letourneur of the genomics platform at the Cochin Institute (GENOM'IC) for quantifying the pJET-ama-1 plasmid.