The acid ceramidase/ceramide axis controls parasitemia in Plasmodium yoelii-infected mice by regulating erythropoiesis

  1. Anne Günther
  2. Matthias Hose
  3. Hanna Abberger
  4. Fabian Schumacher
  5. Ylva Veith
  6. Burkhard Kleuser
  7. Kai Matuschewski
  8. Karl Sebastian Lang
  9. Erich Gulbins
  10. Jan Buer
  11. Astrid Westendorf
  12. Wiebke Hansen  Is a corresponding author
  1. University of Duisburg-Essen, Germany
  2. Freie Universität Berlin, Germany
  3. Humboldt-Universität zu Berlin, Germany

Abstract

Acid ceramidase (Ac) is part of the sphingolipid metabolism and responsible for the degradation of ceramide. As bioactive molecule, ceramide is involved in the regulation of many cellular processes. However, the impact of cell-intrinsic Ac activity and ceramide on the course of Plasmodium infection remains elusive. Here, we use Ac-deficient mice with ubiquitously increased ceramide levels to elucidate the role of endogenous Ac activity in a murine malaria model. Interestingly, ablation of Ac leads to alleviated parasitemia associated with decreased T cell responses in the early phase of Plasmodium yoelii (P. yoelii) infection. Mechanistically, we identified dysregulated erythropoiesis with reduced numbers of reticulocytes, the preferred host cells of P. yoelii, in Ac-deficient mice. Furthermore, we demonstrate that administration of the Ac inhibitor carmofur to wild type mice has similar effects on P. yoelii infection and erythropoiesis. Notably, therapeutic carmofur treatment after manifestation of P. yoelii infection is efficient in reducing parasitemia. Hence, our results provide evidence for the involvement of Ac and ceramide in controlling P. yoelii infection by regulating red blood cell development.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file.; Source Data files have been provided for all Figures and Figure Supplements.

Article and author information

Author details

  1. Anne Günther

    Institute of Medical Microbiology, University of Duisburg-Essen, Essen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Matthias Hose

    Institute of Medical Microbiology, University of Duisburg-Essen, Essen, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0746-5591
  3. Hanna Abberger

    Institute of Medical Microbiology, University of Duisburg-Essen, Essen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Fabian Schumacher

    Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8703-3275
  5. Ylva Veith

    Institute of Biology, Humboldt-Universität zu Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Burkhard Kleuser

    Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Kai Matuschewski

    Institute of Biology, Humboldt-Universität zu Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6147-8591
  8. Karl Sebastian Lang

    Institute of Immunology, University of Duisburg-Essen, Essen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Erich Gulbins

    Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Jan Buer

    Institute of Medical Microbiology, University of Duisburg-Essen, Essen, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7602-1698
  11. Astrid Westendorf

    Institute of Medical Microbiology, University of Duisburg-Essen, Duisburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2121-2892
  12. Wiebke Hansen

    Institute of Medical Microbiology, University of Duisburg-Essen, Essen, Germany
    For correspondence
    wiebke.hansen@uk-essen.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6020-0886

Funding

Deutsche Forschungsgemeinschaft (GRK2098)

  • Karl Sebastian Lang
  • Erich Gulbins
  • Jan Buer
  • Astrid Westendorf
  • Wiebke Hansen

Deutsche Forschungsgemeinschaft (GRK2581)

  • Burkhard Kleuser

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

Reviewing Editor

  1. Malcolm J McConville, The University of Melbourne, Australia

Ethics

Animal experimentation: All experiments were performed in strict accordance with the guidelines of the German Animal Protection Law and approved by the State Agency for Nature, Environment, and Consumer Protection (LANUV), North Rhine-Westphalia, Germany (Az 84-02.04.2015.A474, Az 81-02.04.2018.A302).

Version history

  1. Received: February 17, 2022
  2. Preprint posted: March 10, 2022 (view preprint)
  3. Accepted: September 9, 2022
  4. Accepted Manuscript published: September 12, 2022 (version 1)
  5. Version of Record published: September 22, 2022 (version 2)

Copyright

© 2022, Günther 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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  1. Anne Günther
  2. Matthias Hose
  3. Hanna Abberger
  4. Fabian Schumacher
  5. Ylva Veith
  6. Burkhard Kleuser
  7. Kai Matuschewski
  8. Karl Sebastian Lang
  9. Erich Gulbins
  10. Jan Buer
  11. Astrid Westendorf
  12. Wiebke Hansen
(2022)
The acid ceramidase/ceramide axis controls parasitemia in Plasmodium yoelii-infected mice by regulating erythropoiesis
eLife 11:e77975.
https://doi.org/10.7554/eLife.77975

Share this article

https://doi.org/10.7554/eLife.77975

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