Modulation of host HIF-1α activity and the tryptophan pathway contributes to the anti-Toxoplasma gondii potential of nanoparticles

BACKGROUND: Toxoplasmosis constitutes a large global burden that is further exacerbated by the shortcomings of available therapeutic options, thus underscoring the urgent need for better anti-Toxoplasma gondii therapy or strategies. Recently, we showed that the anti-parasitic action of inorganic nanoparticles (NPs) could, in part, be due to changes in redox status as well as in the parasite mitochondrial membrane potential. METHODS: In the present study, we explored the in vitro mode of action of the anti-T. gondii effect of NPs by evaluating the contributions of host cellular processes, including the tryptophan pathway and hypoxia-inducing factor activity. NPs, at concentrations ranging from 0.01 to 200 µg/ml were screened for anti-parasitic activity. Sulfadiazine and/or pyrimethamine served as positive controls. RESULTS: We found that interplay among multiple host cellular processes, including HIF-1α activity, indoleamine 2,3-dioxygenase activity, and to a larger extent the tryptophan pathway, contribute to the anti-parasitic action of NPs. CONCLUSION: To our knowledge, this is the first study to demonstrate an effect of NPs on the tryptophan and/or kynurenine pathway. GENERAL SIGNIFICANCE: Our findings deepen our understanding of the mechanism of action of NPs and suggest that modulation of the host nutrient pool may represent a viable approach to the development of new and effective anti-parasitic agents.