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

Abstract

BackgroundToxoplasmosis 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.MethodsIn 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.ResultsWe 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.ConclusionTo our knowledge, this is the first study to demonstrate an effect of NPs on the tryptophan and/or kynurenine pathway.General significanceOur 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.

Cellular apoptosis of HFF cells by inorganic nanoparticles not susceptible to modulation by Toxoplasma gondii infection in vitro

“…The biological assay was repeated three times, in triplicate. Selection of doses for the nanoparticles as well as for small molecules was premised on our earlier reports (Adeyemi et al, 2017a(Adeyemi et al, , 2017b(Adeyemi et al, , 2018b) and on preliminary experiments. In all the cases, doses were less than one third of the IC 50 value.…”

“…AuNPs are inert and biocompatible and these have been applied as theranostics as well as for phototherapy (Moses et al, 2016;Rieznichenko et al, 2012) while PtNPs are noted for antioxidant properties that mimic catalase and superoxide dismutase (Sulaiman et al, 2015;Adeyemi et al, 2018a). As a further testament of the increasing popularity of NPs for biomedical applications, the potential of NPs against Toxoplasma gondii infection was recently reported (Adeyemi et al, 2017a;Adeyemi et al, 2017b). In these studies, AgNPs, AuNPs, and PtNPs, exhibited antiparasitic potential which in part was mediated through modulation of host cellular processes such as the downregulation of hypoxia inducing factor 1 protein (HIF-1α) and activation of kynurenine pathway.…”

“…In these studies, AgNPs, AuNPs, and PtNPs, exhibited antiparasitic potential which in part was mediated through modulation of host cellular processes such as the downregulation of hypoxia inducing factor 1 protein (HIF-1α) and activation of kynurenine pathway. Interestingly, NPs and T. gondii affect similar cellular targets such as hypoxia inducing factor 1 (HIF-1α) and tryptophan pathway, particularly indoleamine 2,3-dioxygenase (IDO; rate limiting enzyme in the degradation of tryptophan to form kynurenine) (Blader and Saeji, 2009;Adeyemi et al, 2017b;Wiley et al, 2010;Spear et al, 2006;Zinkernagel et al, 2007).…”

“…Perhaps, there is a growing need to further our understanding of cellular interactions by NPs. These investigations are warranted if we consider some emerging facts; for example, the anti-T. gondii potential of inorganic NPs of silver, gold and platinum has been linked capacity to modulate cellular processes such as the metabolism of tryptophan as well as hypoxia in human foreskin fibroblast (HFF) cells (Adeyemi et al, 2017a(Adeyemi et al, , 2017b. Additionally, investigations have shown that NPs including silver and gold nanoparticles are capable of causing apoptosis in a variety of cell types (Selim and Hendi, 2012;Satapathy et al, 2013).…”

“…Therefore, in the present study we sought to determine how the apoptotic property of NPs are affected in the presence of T. gondii infection and other metabolic modulators such as L-tryptophan, cobalt (II) chloride (CoCl 2 ), 1-Methyl-D-tryptophan (DMT), 3-(5'-Hydroxymethyl-2′-furyl)-1-benzyl indazole (YC-1), trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) and ( ± ) 3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[(phenylmethyl)amino]-2Hnaphtho[2,3-b]pyran-5,10-dione (a naphthoquinone derivative -NPQ). All of these metabolic modulators have been demonstrated to either enhance or restrict the growth of T. gondii elsewhere (Adeyemi et al, 2017b). .…”