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

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.

Acid ceramidase expression reduces IFNγ secretion by mouse CD4+ T cells and is crucial for maintaining B-cell numbers in mice

“…For macrophages, it has, further, been shown that Ac expression is required to contain herpes simplex virus replication with Ac deficiency leading to overwhelming viral replication in mice in vivo ( 25 ). In a mouse model of malaria, Ac deficiency led to decreased parasitemia due to impaired erythropoiesis ( 26 ). A recent study using Ac-floxed mice together with a T-cell-specific Cre (Ac-floxed-CD4Cre) analyzed the impact of Ac expression in T cells on melanoma progression in vivo ( 27 ).…”

“…A recent study using Ac-floxed mice together with a T-cell-specific Cre (Ac-floxed-CD4Cre) analyzed the impact of Ac expression in T cells on melanoma progression in vivo ( 27 ). The authors found that constitutive Ac deficiency in T cells was associated with increased T-cell activation leading to increased accumulation of IFNγ-secreting Th1 cells in tumors and stronger CD8 + T-cell-mediated melanoma cell killing ( 26 ).…”