Marina Maurizio
«Targeting Theileria’s host»
Host metabolism plays a crucial role in the survival of apicomplexan parasites such as Theileria. Our research reveals shared vulnerabilities among these pathogens, supporting the development of host-directed therapies with cross-species potential.
Apicomplexan parasites are intracellular pathogens responsible for some of the world’s most widespread and severe infectious diseases, including malaria (Plasmodium), theileriosis (Theileria), toxoplasmosis (Toxoplasma), and cryptosporidiosis (Cryptosporidium). These parasites have evolved unique strategies to manipulate host cells, such as reprogramming metabolism to support their own growth. This intimate relationship makes apicomplexans particularly challenging to treat, as they reside in protected intracellular niches and rapidly develop resistance to conventional drugs.
Among them, Theileria annulata is a major veterinary pathogen causing significant economic losses in the cattle industry, especially in sub-Saharan Africa and Asia. This parasite infects and transforms bovine immune cells, driving them to proliferate uncontrollably in a cancer-like manner. Current treatments are limited by toxicity, high costs, and drug resistance, highlighting the need for new interventions.
In our recent study, we applied a genome-wide CRISPR/Cas9 screen in Theileria-infected bovine macrophages to identify host genes essential for parasite development but dispensable for the host. This high-throughput approach revealed specific host pathways that the parasite relies on to survive and proliferate. Many of these genes are linked to host metabolism, suggesting that Theileria exploits core metabolic processes for its benefit. One of the most striking findings was the importance of the host heme biosynthesis pathway. Theileria encodes some metabolic enzymes, but it appears to rely on the host’s machinery to fulfil its heme requirements. Disrupting host heme synthesis impaired parasite growth, revealing a vulnerability in the host-parasite interaction.
Crucially, this finding extends beyond Theileria. By comparing our data with metabolic models of the malaria parasite Plasmodium falciparum, we found that Plasmodium liver-stage schizonts also rely on the host heme pathway. Despite targeting different host species and tissues, both parasites share key metabolic dependencies, highlighting conserved vulnerabilities across apicomplexans. This insight opens the door to host-directed therapies, treatments that target host pathways required for parasite survival. Such therapies offer two major advantages: (1) they reduce the chance of resistance, since parasites cannot easily adapt to changes in the host, and (2) they raise the possibility of repurposing existing drugs used to treat human metabolic disorders. Furthermore, targeting the host may also enable a single drug to act against multiple intracellular pathogens, including both veterinary and human parasites.
This work deepens our understanding of Theileria’s dependence on host cells and demonstrates how host-focused research can reveal common weaknesses in closely related parasites. By mapping the host-parasite interface, we lay the foundation for future therapies that are both broad in scope and precise in action.
