Objectives: Malaria is still one of the most life-threatening infectious diseases worldwide. Although it is mainly endemic in tropical and subtropical regions of the world, climate change and globalization are expanding the distribution of Anopheles mosquitoes, the vectors of malaria-causing Plasmodium parasites. The limited availability of anti-malarial drugs and progressive parasite resistances require the development of innovative approaches. Sphingolipids, like ceramide, are important bioactive molecules that mediate fundamental cellular processes. By hydrolysing ceramide, Acid ceramidase (Ac) is a key regulator of cellular ceramide levels. Although Ac and ceramide have been implicated to play a role in several infectious diseases, the function of Ac activity and cell-intrinsic ceramide during malaria remains elusive. Hence, we aimed to investigate the impact of the Ac/ceramide system on Plasmodium infection.

Methods: By using Ac-deficient mice with ubiquitously increased ceramide levels, we elucidated the role of endogenous Ac activity during Plasmodium yoelii (P. yoelii) infection, a murine malaria model. Moreover, we investigated the effect of preventive and therapeutic treatment with the Ac inhibitor carmofur on the infection.

Results: Interestingly, global ablation of Ac resulted in alleviated parasitemia associated with diminished T cell responses in the early phase of P. yoelii infection. Mechanistically, we identified dysregulated erythropoiesis in Ac-deficient mice, resulting in reduced frequencies of reticulocytes, the preferred host cells of P. yoelii parasites. Furthermore, we demonstrated that inhibition of Ac by carmofur treatment of wild type mice has similar effects on the course of P. yoelii infection and on red blood cell development. Most importantly, also therapeutic carmofur administration after an established P. yoelii infection efficiently dampened parasitemia.

Conclusion: Summarised, our study indicates the involvement of the Ac/ceramide axis in controlling Plasmodium infection. Thus, pharmacological inhibition of Ac might represent a novel therapeutic strategy to combat malaria and other infectious diseases caused by reticulocyte-prone pathogens.