Evaluation of current and emerging anti-malarial medicines for inhibition of<i>Toxoplasma gondii</i>growth in vitro

Radke, Joshua B.; Burrows, Jeremy N.; Goldberg, Daniel E.; Sibley, L. David

doi:10.1101/316455

Cited by 5 publications

(7 citation statements)

References 87 publications

(69 reference statements)

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“…A number of other chemical libraries have been tested against T. gondii to possibly identify new therapeutic compounds [118][119][120][121] , including all FDA approved drugs seeking compounds for repurposing. In addition, screening of compounds that are active against malaria identified relatively few candidates that were effective against T. gondii 122 . Atovaquone 123 and ELQ-300 124 are effective against tachyzoites and both compounds reduced tissue cyst numbers in chronically infected mice, but complete cure was not achieved.…”

Section: Dormant Forms Of Toxoplasma -The Sporozoite and Bradyzoitementioning

confidence: 99%

Protozoan persister-like cells and drug treatment failure

et al. 2019

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Antimicrobial treatment failure threatens our ability to control infections. In addition to antimicrobial resistance, treatment failures are increasingly understood to derive from cells that survive antibiotic treatment without selection of genetically heritable mutations. Parasitic protozoa, such as Plasmodium species that cause malaria, Toxoplasma gondii and Kinetoplastid protozoa, including Trypanosoma cruzi and Leishmania spp., cause millions of deaths globally. These organisms can evolve drug resistance and they also exhibit phenotypic diversity, including the formation of quiescent or dormant forms that contribute to the establishment of long-term infections that are refractory to drug treatment, which we refer to as persister-like cells. In this Review, we discuss protozoan persister-like cells that have been linked to persistent infections and discuss their impact on therapeutic outcomes following drug treatment.

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Section: Dormant Forms Of Toxoplasma -The Sporozoite and Bradyzoitementioning

confidence: 99%

Protozoan persister-like cells and drug treatment failure

et al. 2019

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“…Using T. gondii to understand apicomplexan DHA susceptibility. Previous studies have demonstrated the susceptibility of T. gondii to ART and its derivatives [35][36][37] . To establish the susceptibility of T. gondii to DHA in our assays, we treated intracellular parasites with varying concentrations of DHA or pyrimethamine (the frontline treatment for toxoplasmosis) for 24 h. Parasite viability was measured by counting the number of vacuoles containing two or more parasites in vehicle-or drugtreated conditions.…”

Section: Resultsmentioning

confidence: 99%

Genetic screens reveal a central role for heme metabolism in artemisinin susceptibility

et al. 2020

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Artemisinins have revolutionized the treatment of Plasmodium falciparum malaria; however, resistance threatens to undermine global control efforts. To broadly explore artemisinin susceptibility in apicomplexan parasites, we employ genome-scale CRISPR screens recently developed for Toxoplasma gondii to discover sensitizing and desensitizing mutations. Using a sublethal concentration of dihydroartemisinin (DHA), we uncover the putative transporter Tmem14c whose disruption increases DHA susceptibility. Screens performed under high doses of DHA provide evidence that mitochondrial metabolism can modulate resistance. We show that disrupting a top candidate from the screens, the mitochondrial protease DegP2, lowers porphyrin levels and decreases DHA susceptibility, without significantly altering parasite fitness in culture. Deleting the homologous gene in P. falciparum, PfDegP, similarly lowers heme levels and DHA susceptibility. These results expose the vulnerability of heme metabolism to genetic perturbations that can lead to increased survival in the presence of DHA.

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“…The parasite is present in one-third of the human population worldwide and is a significant health concern for immunocompromised individuals (10–13). At present, there is no vaccine or drug available to prevent or completely cure toxoplasmosis in humans (14, 15). NK cells are involved in innate immunity during acute T. gondii infection and are critical for early protection (16, 17).…”

Section: Introductionmentioning

confidence: 99%

“…NK cells are clearly important for early control of T. gondii infection, yet their role in long-term immunity has not been addressed. This is clinically important to understand because there currently is no vaccine that elicits sterilizing immunity to the parasite (15, 27). A vaccine targeting the stimulation of NK cells in addition to CD8+ T cells could therefore be more beneficial long-term.…”

Section: Introductionmentioning

confidence: 99%

The IL-12– and IL-23–Dependent NK-Cell Response is Essential for Protective Immunity Against SecondaryToxoplasma GondiiInfection

Ivanova

Mundhenke

Gigley

2019

Preprint

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22Natural Killer (NK) cells can develop memory-like features and contribute to long-term 23 immunity in mice and humans. NK cells are critical for protection against acute T. 24 gondii infection. However, whether they contribute to long-term immunity in response to this 25 parasite is unknown. We used a vaccine challenge model of parasite infection to address this 26 question and to define the mechanism by which NK cells are activated during secondary parasite 27 infection. We found NK cells were required for control of secondary infection. NK cells 28 increased in number at the infection site, became cytotoxic and produced IFNγ. Adoptive transfer 29 and NK-cell fate mapping revealed that T. gondii−experienced NK cells were not intrinsically 30 different from naïve NK cells with respect to their long-term persistence and ability to protect. 31 Thus, they did not develop memory-like characteristics. Instead, a cell-extrinsic mechanism may 32 control protective NK-cell responses during secondary infection. To test the involvement of a 33 cell-extrinsic mechanism, we used anti-IL-12p70 and IL-12p35 − / − mice and found that the 34 secondary NK-cell response was not fully dependent on IL-12. IL-23 depletion with anti-IL-35 23p19 in vivo significantly reduced the secondary NK-cell response, suggesting that both IL-12 36 and IL-23 were involved. Anti-IL-12p40 treatment, which blocks both IL-12 and IL-23, 37 eliminated the protective secondary NK-cell response, supporting this hypothesis. Our results 38 define a previously unknown protective role for NK cells during secondary T. gondii infection 39 that is dependent on IL-12 and IL-23. 40 to T. gondii. In the absence of CD4+ T cells, IFNγ produced by NK cells promotes CD8+ T-cell 65 activation (21). In the absence of CD8+ T cells, NK-cell IFNγ contributes to the activation of 66 CD4+ T cells (22). In addition to cytokine production, NK cells produce perforin and granzymes 67 in response to the parasite and its subcellular components (23)(24)(25)(26). 68 NK cells are clearly important for early control of T. gondii infection, yet their role in 69 long-term immunity has not been addressed. This is clinically important to understand because 70 there currently is no vaccine that elicits sterilizing immunity to the parasite (15, 27). A vaccine 71 targeting the stimulation of NK cells in addition to CD8+ T cells could therefore be more 72 beneficial long-term. In addition, T. gondii infection causes health complications in 73 immunodeficient patients, many of whom are T-cell deficient (e.g., HIV patients) (11). 74Discovering new ways to utilize NK cells could be therapeutically beneficial for these patients. 75In this study, we aimed to find whether NK cells contribute to long-term immunity 76 against T. gondii in a vaccine challenge setting. We also investigated whether NK cells 77 developed memory-like features in response to this vaccination. Lastly, we tested mechanisms 78 involved in the activation of NK cells during secondary challenge. We demonstrate that NK cells 79 a...

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Evaluation of current and emerging anti-malarial medicines for inhibition ofToxoplasma gondiigrowth in vitro

Cited by 5 publications

References 87 publications

Protozoan persister-like cells and drug treatment failure

Protozoan persister-like cells and drug treatment failure

Genetic screens reveal a central role for heme metabolism in artemisinin susceptibility

The IL-12– and IL-23–Dependent NK-Cell Response is Essential for Protective Immunity Against SecondaryToxoplasma GondiiInfection

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