Two tick-borne parasites, *Theileria annulata* and *Theileria parva*, hijack cattle white blood cells and turn them into immortal, cancer-like cells—but they do so by commandeering different molecular pathways. This matters because these parasites kill up to 100% of infected livestock in tropical and sub-tropical regions, and current control methods—toxic acaricides, drugs facing resistance, and difficult-to-deploy vaccines—are failing. Animals that survive remain carriers, spreading the parasite. Researchers know both species can transform B cells, but *T. annulata* also transforms monocytes and macrophages, while *T. parva* transforms T cells. No one has systematically compared the molecular factors behind these similar yet distinct outcomes. If this project succeeds, it will produce the first comprehensive comparative map of the host genes and regulatory variants that control infection by both parasites. That knowledge could reveal new drug targets or vaccine strategies that work across *Theileria* species, reducing livestock losses and improving food security in affected regions. Because the transformed cells mimic a malignant phenotype without damaging host DNA, the work may also offer fundamental insights into cancer biology—a purely curiosity-driven bonus with potential long-term payoffs for understanding uncontrolled cell growth.
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Theileria are amongst the most impactful tick-borne parasites of livestock in tropical and sub-tropical regions. Theileria annulata and Theileria parva are the most prevalent Theileria species causing reduced productivity and 100% mortality in tropical and sub-tropical livestock systems. Current Theileria control strategies, which include acaricides, chemotherapy, and live attenuated vaccines, have many limitations including environmental toxicity, drug resistance, and difficulty to produce and deploy. Additionally, animals that recover from Theileria infections remain carriers and play a significant role in parasite transmission in endemic areas. Therefore, developing novel effective Theileria control strategies is an important priority for veterinary research. T. annulata and T. parva infection outcomes have many similarities, including the transformation of infected white blood cells into immortalized cancerous-like cells - which the parasites achieve by co-opting different host cell signalling pathways. However, although both parasite species can transform B cells, T. annulata and T. parva can also transform and replicate in monocytes/macrophages and T cells, respectively. Currently, there are gaps in our knowledge of the molecular factors that underpin this similar and distinct infection outcomes in B cells, monocytes/macrophages, and T cells. For example, do both parasites co-opt the same host cell signalling pathways to transform B cells? Second, what are the unique host cell signalling pathways co-opted by T. annulata and T. parva to enable parasite species-specific transformation of macrophages/monocytes and T. cells? We recently, identified a region in the genome linked with tolerance to T. parva in native cattle in T. parva-endemic areas of East Africa. Interestingly, we observed a high frequency of the same T. parva tolerance haplotype in native cattle breeds and Asian buffalos in India, where T. annulata, not T. parva, is prevalent, suggesting that the same host-derived molecular factors control T. annulata and T. parva infection outcomes. Guided by these observations and strong preliminary data, we aim to address current gaps in our knowledge on how Theileria subvert normal host cellular processes to facilitate parasite replication, and how these host-parasite interactions may vary between T. annulata and T. parva. We will do this by deploying parasitology and unbiased genetic screening protocols that are well-established in our labs to pursue the following objectives: 1. Identify how host regulatory genetic variants control gene expression in T. annulata-infected bovine cells. 2. Identify how host genes control the transformation and proliferation of T. annulata-infected cells. 3. Identify how parasite species-specific and non-specific host-derived factors control T. annulata and T. parva infection. Collectively, our proposal will broadly impact the Theileria field by providing the first comprehensive comparative analysis of the molecular events controlling T. annulata and T. parva infection outcomes. The studies have the potential to uncover novel insights that can be exploited to combat these parasites. Theileria transformed cells exhibit a malignant phenotype, but without damage to host cell DNA. Therefore, besides Theileria biology, the project can also contribute to the field of cancer biology.
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