A reversible Warburg effect is induced by Theileria parasites to transform host leukocytes

Notable characteristics of growing tumor cells are their increased glycolytic rate and their decreased oxidative respiration, irrespective of oxygen availability. This key hallmark of cancers is known as the " Warburg effect ". 1 In the emerging field linking glucose metabolism and cancer progression, there is much debate about the causal role of the Warburg effect. It is unclear whether the Warburg effect is merely a secondary side effect of cancer transformation, or whether it is a direct initiator of tumorigenesis or essential for maintenance. Resolving this conundrum is an important research and clinical need, sparking intense investigation into the molecular features of the Warburg effect. To contribute to this debate, we exploited a unique model for cancer transformation: bovine leukocytes infected and transformed by the eukaryotic intra-cellular parasite Theileria. We studied the metabolic relationship between host and parasite cells. Theileria parasites of the Apicomplexa phylum infect bovine leukocytes and turn them into invasive, cancer-like cells in a lymphoproliferative disease. Theileria parasites residing in the host cell cytoplasm manipulate and functionally rewire the host cell. 4 We hypothesized that the intimate host-parasite relationship might disrupt host cell metabolism and contribute to the cancer-like phenotypes. We recently described an ingenious mechanism by which the intra-cellular parasite induces a Warburg-like effect in infected host cells, associated with a shift from oxidative phosphorylation to aerobic glycolysis. 5 We observed that the parasite inside the host leukocyte induces, directly or indirectly, elevated production of reactive oxygen species (ROS). This increase in oxidative stress is associated with stabilization and activation of the hypoxia-inducible factor 1 α (HIF1α) that plays a pivotal role in the establishment/ maintenance of the Warburg effect in diverse cancers. 6 We speculate that the major shift in cellular glucose demands could be the consequence of increased nutrient requirements of the intracellular parasite. Indeed, the shift in host glucose metabolism could constitute an efficient way of providing critical nutrients (for example, for nucleotide and lipid synthesis pathways) that are required for Theileria proliferation and maintenance within the host cell. Thus, the metabolite requirements of the intra-cellular parasite might inadvertently lead to metabolic reprogramming of the host cell. Our recent findings also suggest that Theileria may secrete proteins into host compartments, which can rewire glucose metabolism through HIF1α regulation, thereby directly targeting actors of metabolic homeostasis (unpublished data). An intriguing particularity of the Theileria model is its reversibility. Elimination of the parasite, using …