PT Unknown AU Günther, A TI Role of Acid Ceramidase during Plasmodium Infection and Tumorigenesis PD 10 PY 2022 DI 10.17185/duepublico/77056 LA en AB Acid ceramidase (Ac) is part of the sphingolipid metabolism. By hydrolysing ceramide to sphingosine, which is further degraded to sphingosine-1-phosphate (S1P), Ac is a key regulator of the sphingolipid rheostat. Ceramide is a bioactive molecule involved in many cellular processes. It forms ceramide-enriched platforms at the plasma membrane, enabling receptor clustering and induction of signalling cascades. Studies show that Ac and ceramide play a role in several infectious diseases. However, their impact on malaria-causing Plasmodium (P.) infection remains elusive. Using global and cell type-specific Ac-deficient mice, the present study aimed to investigate the role of host cell-intrinsic Ac activity and ceramide on the course of P. yoelii infection. Interestingly, systemic ablation of Ac led to reduced parasitemia and decreased T cell responses in the initial phase of infection. However, analysis of cell type-specific Ac-deficient mice showed that cell-intrinsic ceramide levels in myeloid cells and T cells did not significantly affect the course of P. yoelii infection. Instead, a dysregulated erythropoiesis with reduced numbers of reticulocytes, the target cells of P. yoelii parasites, was identified as underlying mechanism of alleviated parasitemia and delayed T cell responses in Ac KO mice. Well in line, pharmacological inhibition of Ac by carmofur in P. yoelii-infected wild type mice had similar effects on parasitemia and erythropoiesis. Noteworthy, even therapeutic application of carmofur after manifestation of the infection was efficient in reducing the parasite burden. In addition to its role in parasitic infections, the function of Ac in T cell-mediated immune responses during tumorigenesis was investigated. While the ceramide-generating enzyme acid sphingomyelinase has been extensively studied in T cells, the role of Ac in T cells is largely unknown. Therefore, T cell-specific Ac-deficient mice were used to analyse the impact of Ac on T cell function. In vitro experiments revealed increased T cell receptor signalling in both, Ac-deficient CD4+ and CD8+ T cells, accompanied by an enhanced cytotoxic phenotype. Moreover, antigen-specific Ac-deficient CD8+ T cells exhibited an increased killing capacity in vitro. Strikingly, T cell-specific Ac ablation led to an elevated anti-tumoral immune response, resulting in decreased melanoma progression in vivo. In summary, this study provides evidence for the involvement of Ac and cell-endogenous ceramide in modulating the course of P. yoelii infection and T cell immune responses during tumorigenesis. ER