The acid ceramidase/ceramide axis controls parasitemia in Plasmodium yoelii-infected mice by regulating erythropoiesis
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Evaluation Summary:
This study provides evidence that murine acid ceramidase (Ac) is required for normal erythropoiesis and development of rodent malaria. The findings are of interest in understanding molecular processes involved in regulating erythropoiesis, as well as the potential to develop host-directed therapies for malarial parasites that target human reticulocytes.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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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 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 wildtype 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.
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Evaluation Summary:
This study provides evidence that murine acid ceramidase (Ac) is required for normal erythropoiesis and development of rodent malaria. The findings are of interest in understanding molecular processes involved in regulating erythropoiesis, as well as the potential to develop host-directed therapies for malarial parasites that target human reticulocytes.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
The authors show that the development of non-lethal rodent parasite Plasmodium yoelii is transiently retarded in Ac-deficient mice. While loss of Ac leads to changes in T cell responses, these changes are not responsible for reduced parasitemia and splenomegaly, as selective deletion of Ac in either T-cells or macrophages had no effect on parasite development. Instead, loss of acid ceramidase and accumulation of ceramide and SM were found to be associated with reduced reticulocyte levels, the major host cell for P. yoelii. A similar, but less dramatic, reduction in parasitemia was also achieved by treatment of P. yoelii-infected mice with the Ac inhibitor, carmofur. The findings suggest that it may be possible to safely modulate erythropoiesis and reticulocyte levels to reduce infections caused by human …
Reviewer #1 (Public Review):
The authors show that the development of non-lethal rodent parasite Plasmodium yoelii is transiently retarded in Ac-deficient mice. While loss of Ac leads to changes in T cell responses, these changes are not responsible for reduced parasitemia and splenomegaly, as selective deletion of Ac in either T-cells or macrophages had no effect on parasite development. Instead, loss of acid ceramidase and accumulation of ceramide and SM were found to be associated with reduced reticulocyte levels, the major host cell for P. yoelii. A similar, but less dramatic, reduction in parasitemia was also achieved by treatment of P. yoelii-infected mice with the Ac inhibitor, carmofur. The findings suggest that it may be possible to safely modulate erythropoiesis and reticulocyte levels to reduce infections caused by human malaria parasites that also target reticulocytes (e.g. P. vivax). While the results are clearly described, further evidence is needed to support the main conclusion that dysregulation of erythropoiesis is due accumulation of ceramide/SM. In particular, loss of Ac could potentially leads to changes in sphingosine/S1P levels, which should be investigated. Similarly, the effect of carmofur on parasite growth in vitro should also be assessed.
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Reviewer #2 (Public Review):
Using an experimental malaria model employing infection of mice with P.yoelii the authors aimed to study the effect of Acid ceramidase (Ac) on the outcome of infection using inducible KO mice. The present study extends their previous observations on T cell specific function of Ac. The authors provide evidence that an early reduction of parasitemia could be observed in Ac KO mice but differences vanishes at later time points. Infected Ac mice displayed a decreased T cell activation. Using different Cre mice the authors showed that neither Ac deficiency in the T cell or myeloid compartment is sufficient to reduce the parasitemia. Instead they found that Ac deficiency per se is influencing erythropoiesis. As a result a decrease of reticulocytes, the preferable target of P. yoelii, is accompanied by a reduced …
Reviewer #2 (Public Review):
Using an experimental malaria model employing infection of mice with P.yoelii the authors aimed to study the effect of Acid ceramidase (Ac) on the outcome of infection using inducible KO mice. The present study extends their previous observations on T cell specific function of Ac. The authors provide evidence that an early reduction of parasitemia could be observed in Ac KO mice but differences vanishes at later time points. Infected Ac mice displayed a decreased T cell activation. Using different Cre mice the authors showed that neither Ac deficiency in the T cell or myeloid compartment is sufficient to reduce the parasitemia. Instead they found that Ac deficiency per se is influencing erythropoiesis. As a result a decrease of reticulocytes, the preferable target of P. yoelii, is accompanied by a reduced parasitemia. This effect can be in part recapitulated by carmofur which also reduced reticulocytes. The authors discussed this as a possible new therapeutic option. However, in light of the side effects of carmofur a possible therapeutic remained ambiguous. In conclusion malaria infection and its outcome was useful to detect a new phenotype of Ac KO mice. However how Ac deficiency influences erythropoiesis (even in absence of infection) remained unclear.
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