Toxoplasmosis: leveraging active purine nucleoside uptake as new therapeutic strategy.

The Apicomplexan parasite Toxoplasma gondii is a widespread opportunistic pathogen infecting up to one-third of the entire world’s population. Although acute infections are generally asymptomat, great immunocompromised patients are at great risk, for whom a disseminated disease leads to a life-threatening condition. Furthermore, infections can result in severe congenital defects, making toxoplasmosis a threatening condition for pregnant. Parasites escape the immune response by entering into a chronic disease state, acting as a reservoir for later reactivation of acute disease, should the patient’s immune-vigilance deteriorate. Current drugs fail to provide a cure for toxoplasmosis and cause significant side-effects, resistance to first-line sulfonamides is problematic. Additionally, malicious pricing practices have endangered the affordability and access to first-line drugs. Purine salvage is essential for T. gondii as it lacks the ability to produce its own purine metabolites, which are required in large amounts for its fast replication. As such, it expresses highly efficient, active purine transporters with broad substrate recognition. In addition, the parasite has an elaborate, high capacity network of purine metabolism enzymes. This proposal aims to study and exploit active uptake and activation of purine nucleoside analogues by T. gondii as a therapeutic strategy.