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High throughput screen identifies IFN-γ-dependent inhibitors of Toxoplasma gondii growth

Joshua B. Radke, Kimberly L. Carey, Subrata Shaw, Shailesh R. Metkar, Carol Mulrooney, Jennifer P. Gale, Joshua A. Bittker, Robert Hilgraf, Eamon Comer, Stuart L. Schreiber, Herbert W. Virgin, Jose R. Perez, View ORCID ProfileL. David Sibley
doi: https://doi.org/10.1101/336818
Joshua B. Radke
Department of Molecular Microbiology, Washington University Sch. Med., St Louis, MO 63110
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Kimberly L. Carey
Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142
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Subrata Shaw
Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142
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Shailesh R. Metkar
Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142
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Carol Mulrooney
Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142
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Jennifer P. Gale
Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142
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Joshua A. Bittker
Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142
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Robert Hilgraf
Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142
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Eamon Comer
Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142
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Stuart L. Schreiber
Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142
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Herbert W. Virgin
Department of Pathology and Immunology, Washington University Sch. Med., St. Louis, MO 63110
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Jose R. Perez
Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142
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L. David Sibley
Department of Molecular Microbiology, Washington University Sch. Med., St Louis, MO 63110
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  • ORCID record for L. David Sibley
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Abstract

Toxoplasma gondii is an obligate intracellular parasite capable of causing severe disease due to congenital infection and in patients with compromised immune systems. Control of infection is dependent on a robust Th1 type immune response including production of interferon gamma (IFN-γ), which is essential for control. IFN-γ activates a variety of anti-microbial mechanisms in host cells, which are then able to control intracellular parasites such as T. gondii. Despite the effectiveness of these pathways in controlling acute infection, the immune system is unable to eradicate chronic infections that can persist for life. Similarly, while antibiotic treatment can control acute infection, it is unable to eliminate chronic infection. To identify compounds that would act synergistically with IFN-γ, we performed a high-throughput screen of diverse small molecule libraries to identify inhibitors of T. gondii. We identified a number of compounds that inhibited parasite growth in vitro at low μM concentrations and that demonstrated enhanced potency in the presence of low level of IFN-γ. A subset of these compounds act by enhancing the recruitment of LC3 to the parasite-containing vacuole, suggesting they work by an autophagy-related process, while others were independent of this pathway. The pattern of IFN-γ-dependence was shared among the majority of analogs from 6 priority scaffolds and analysis of structure activity relationships for one such class revealed specific stereochemistry associated with this feature. Identification of these IFN-γ-dependent leads may lead to development of improved therapeutics due to their synergistic interactions with immune responses.

  • Abbreviations used

    IFN-γ
    interferon gamma
    PYR
    pyrimethamine
    LC3
    light chain 3
    FLUC
    firefly luciferase
    EC
    effective concentration
    GFP
    green fluorescent protein
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    Posted June 02, 2018.
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    High throughput screen identifies IFN-γ-dependent inhibitors of Toxoplasma gondii growth
    Joshua B. Radke, Kimberly L. Carey, Subrata Shaw, Shailesh R. Metkar, Carol Mulrooney, Jennifer P. Gale, Joshua A. Bittker, Robert Hilgraf, Eamon Comer, Stuart L. Schreiber, Herbert W. Virgin, Jose R. Perez, L. David Sibley
    bioRxiv 336818; doi: https://doi.org/10.1101/336818
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    High throughput screen identifies IFN-γ-dependent inhibitors of Toxoplasma gondii growth
    Joshua B. Radke, Kimberly L. Carey, Subrata Shaw, Shailesh R. Metkar, Carol Mulrooney, Jennifer P. Gale, Joshua A. Bittker, Robert Hilgraf, Eamon Comer, Stuart L. Schreiber, Herbert W. Virgin, Jose R. Perez, L. David Sibley
    bioRxiv 336818; doi: https://doi.org/10.1101/336818

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