1. Cell Biology
  2. Microbiology and Infectious Disease
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Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy

  1. John D Chan
  2. Timothy A Day
  3. Jonathan S Marchant  Is a corresponding author
  1. Iowa State University, United States
  2. Medical College of Wisconsin, United States
Research Article
  • Cited 6
  • Views 827
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Cite this article as: eLife 2018;7:e35755 doi: 10.7554/eLife.35755

Abstract

Conventional approaches for antiparasitic drug discovery center upon discovering selective agents that adversely impact parasites with minimal host side effects. Here, we show that agents with a broad polypharmacology, often considered 'dirtier' drugs, can have unique efficacy if they combine deleterious effects on the parasite with beneficial actions in the host. This principle is evidenced through a screen for drugs to treat schistosomiasis, a parasitic flatworm disease that impacts over 230 million people. A target-based screen of a Schistosoma serotoninergic G protein coupled receptor yielded the potent agonist, ergotamine, which disrupted worm movement. In vivo, ergotamine decreased mortality, parasite load and intestinal egg counts but also uniquely reduced organ pathology through engagement of host GPCRs that repressed hepatic stellate cell activation, inflammatory damage and fibrosis. The unique ability of ergotamine to engage both host and parasite GPCRs evidences a future strategy for anthelmintic drug design that coalesces deleterious antiparasitic activity with beneficial host effects.

Article and author information

Author details

  1. John D Chan

    Department of Biomedical Sciences, Iowa State University, Ames, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Timothy A Day

    Department of Biomedical Sciences, Iowa State University, Ames, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9037-6540

  3. Jonathan S Marchant

    Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, United States
    For correspondence
    JMarchant@mcw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6592-0877

Funding

National Institutes of Health (R21AI25821)

  • Jonathan S Marchant

National Institutes of Health (R21AI130642)

  • Jonathan S Marchant

National Institutes of Health (R01GM088790)

  • Jonathan S Marchant

National Institutes of Health (F32AI124598)

  • John D Chan

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments followed ethical regulations approved by the Medical College of Wisconsin IACUC committee (AUA00006079) and additionally reviewed in the context of extramural funding by the National Institutes of Health (NIAID).

Reviewing Editor

  1. Dominique Soldati-Favre, University of Geneva, Switzerland

Publication history

  1. Received: February 8, 2018
  2. Accepted: July 24, 2018
  3. Accepted Manuscript published: July 30, 2018 (version 1)
  4. Version of Record published: August 16, 2018 (version 2)

Copyright

© 2018, Chan et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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