S2E_Thei

Parasites living within mammalian cells develop sophisticated strategies to escape host defence mechanisms and to hijack host cell processes for their own benefit. Our study focuses on the fascinating features of the interaction between Theileria parasites and their leukocyte hosts and asks how signalling pathways and epigenetic regulators contribute to the parasite’s ability to manipulate the host cell phenotype. Theileria, a member of the phylum Apicomplexa that includes the deadly pathogens Plasmodium and Toxoplasma, is the only eukaryote known to transform its host cell and constitutes a unique model system to explore parasite-host interactions. Theileria-infected leukocytes become immortalised, proliferate in the absence of growth factors and are characterised by a lethal invasive potential. In contrast to most transformation processes, which involve permanent changes in the cell’s genome, Theileria-induced transformation is reversible by the theilericidal drug Buparvaquone. Thus, this model offers a unique system to study the signalling and epigenetic mechanisms underlying the parasite-induced changes in pathological cellular phenotypes. Our ambitious project brings together parasitologists, cell biologists and epigeneticists to investigate changes in host gene expression induced by intracellular Theileria and the mechanisms linked to gene regulation and transcription. We will subsequently investigate the effects on cellular phenotypes with a specific focus on the invasive capacity of infected cells using in vitro and in vivo models. The intimate interaction between the parasite and host leukocytes offers a unique opportunity to understand host-pathogen interplay in terms of signalling and chromatin regulation. Our project is built on recent data generated in the three partner laboratories: The Langsley lab has recently documented gene expression regulated by TGF-beta signalling in Theileria infected leukocytes; the Weitzman lab has discovered chromatin modifiers and microRNAs contribute to parasite-induced transcriptional changes; and the Baumgartner group has described dramatic effects on the host cell cytoskeleton influencing migration and invasion. The current proposal (S2E-Thei: Signalling to Epigenetics induced by Theileria) plans to build on these exciting results to develop an integrated model for understanding the link between signal transduction and epigenome remodelling and how these mechanisms lead to parasite-induced leukocyte invasion. The four year project is coordinated around three experimental phases: the first will focus on understanding the role of the TGF-beta signalling pathway, investigating a network of 76 TGF-beta-regulated genes in infected leukocytes; the second concentrates on the study of chromatin modifiers and microRNAs associated with Theileria transformation.; and the third will attempt to bring these findings together to determine how chromatin changes can influence the signalling process and impact the invasive phenotype in vitro and in vivo. These studies will be the first to take such an approach to dissect host-parasite interactions and understand how Theileria manipulates host gene expression and the host epigenome to affect host cell phenotypes. In addition, our results should provide insights into the role of TGF-beta signalling and epigenetic phenomena in tumour cell invasion. As the TGF-beta pathway and the Chromatin modifying enzymes are potentially ‘drugable’, these results should lead to avenues developing small molecule inhibitors of these pathways, which could be used as anti-cancer and anti-parasite therapeutics.