Effective adjunctive therapy by an innate defense regulatory Peptide in a preclinical model of severe malaria

Ariel Achtman, Sandra Pilat, Charity Law, David Lynn, Laure Janot, Matt Mayer, Shuhua Ma, Jason Kindrachuk, B. Finlay, Fiona Brinkman, Gordon Smyth, Robert Hancock, Louis Schofield

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    Abstract

    Case fatality rates for severe malaria remain high even in the best clinical settings because antimalarial drugs act against the parasite without alleviating life-threatening inflammation. We assessed the potential for host-directed therapy of severe malaria of a new class of anti-inflammatory drugs, the innate defense regulator (IDR) peptides, based on host defense peptides. The Plasmodium berghei ANKA model of experimental cerebral malaria was adapted to use as a preclinical screen by combining late-stage intervention in established infections with advanced bioinformatic analysis of early transcriptional changes in co-regulated gene sets. Coadministration of IDR-1018 with standard first-line antimalarials increased survival of infected mice while down-regulating key inflammatory networks associated with fatality. Thus, IDR peptides provided host-directed adjunctive therapy for severe disease in combination with antimalarial treatment.

    Original languageEnglish
    Article number135ra64
    Pages (from-to)135ra64
    Number of pages10
    JournalScience Translational Medicine
    Volume4
    Issue number135
    DOIs
    Publication statusPublished - 2012

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    Achtman, A., Pilat, S., Law, C., Lynn, D., Janot, L., Mayer, M., Ma, S., Kindrachuk, J., Finlay, B., Brinkman, F., Smyth, G., Hancock, R., & Schofield, L. (2012). Effective adjunctive therapy by an innate defense regulatory Peptide in a preclinical model of severe malaria. Science Translational Medicine, 4(135), 135ra64. [135ra64]. https://doi.org/10.1126/scitranslmed.3003515