Toxoplasma gondii stands among nature’s most successful eukaryotic pathogens, a status achieved through refined mechanisms for intracellular survival that enable pan-vertebrate host tropism. This ecological dominance derives principally from evolutionary refinements in metabolic plasticity, a modular integration of de novo biosynthesis with high-efficiency nutrient scavenging systems. The pyrimidine biosynthesis pathway is indispensable for robust parasite proliferation. Our previous work demonstrated that exogenous uracil supplementation bypasses the DHO deficiency-induced growth restriction. Here, we reconfirm the functional pyrimidine rescue using an ATC -knockout parasite line, identifying a protective salvage route that maintains pyrimidine pool homeostasis. Pharmacological suppression of T. gondii growth with NBMPR, a potent hENT1 antagonist, confirms that host hENT1 serves as a critical conduit for pyrimidine and purine acquisition by the parasite. Evolutionary analysis identifies Tg ENT1, Tg ENT3, TGGT1₃59630, and Tg AT1 as hENT1 homologs, with Tg ENT1 demonstrating the strongest phylogenetic clustering with hENT1. The computational models predict interactions between Tg ENT1 and a spectrum of ligands (NBMPR, nucleosides, and nucleobases), supporting its classification as a broad-specificity nucleoside/nucleobase transporter, consistent with the function of hENT1. The genetic intractability of Tg ENT1, however, indicates that it likely plays an essential role in parasite proliferation. Our study reveals that NBMPR-mediated inhibition of both Tg ENT1 and hENT1 disrupts a hierarchical transport cascade essential for T. gondii to acquire pyrimidines and purines from the host, highlighting the promise of a strategy that simultaneously targets both parasite and host nutrient acquisition pathways for improved anti-toxoplasmosis therapy.
Pan et al. (Mon,) studied this question.