Adenosine deprivation modulates purine metabolism and enhances Trichomonas vaginalis cytotoxicity.

Trichomonas vaginalis, the causative agent of human trichomoniasis, relies on host-derived nutrients such as purines and glucose to support survival during infection. As an auxotrophic protozoan, T. vaginalis is incapable to synthesize purine nucleotides de novo and depends entirely on salvage mechanisms, particularly those involving adenosine. However, how nutrient availability modulates the parasite's virulence and purine metabolism remains unclear. Here, we demonstrate that serum and glucose limitation modulate the purine metabolism in T. vaginalis, enhancing extracellular nucleotide hydrolysis by ectonucleoside triphosphate diphosphohydrolase (NTPDase). Serum limitation, a condition that mimics reduced adenosine levels, increased the cytotoxicity of T. vaginalis towards human vaginal epithelial cells (HVECs). When adenosine was added to the culture, it reversed the increase in NTPDase activity and cytotoxicity caused by serum limitation. The protective effect promoted by adenosine during co-incubation of serum-limited T. vaginalis and HVECs was reduced by dipyridamole, possibly indicating a critical role for adenosine uptake by the parasites. Gene expression analysis revealed differential regulation of T. vaginalis equilibrative nucleoside transporter genes, with downregulation under serum limitation and upregulation under glucose restriction, suggesting an adaptative transcriptional response to stress in nutrient availability. These findings reveal that adenosine deprivation modulates purine metabolism in T. vaginalis and enhances parasite cytotoxicity. Furthermore, our results uncover adenosine as a pivotal regulator of T. vaginalis virulence under metabolic stress and highlight purine salvage pathways and nucleoside transport as promising targets for therapeutic intervention against trichomoniasis.