The acid ceramidase/ceramide axis controls parasitemia in Plasmodium yoelii-infected mice by regulating erythropoiesis
- University of Duisburg-Essen, Germany
- Freie Universität Berlin, Germany
- 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
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.
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).
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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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
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