Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany.
Elife. 2022 Sep 12;11:e77975. doi: 10.7554/eLife.77975.
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 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 infection. Mechanistically, we identified dysregulated erythropoiesis with reduced numbers of reticulocytes, the preferred host cells of , in Ac-deficient mice. Furthermore, we demonstrate that administration of the Ac inhibitor carmofur to wildtype mice has similar effects on infection and erythropoiesis. Notably, therapeutic carmofur treatment after manifestation of infection is efficient in reducing parasitemia. Hence, our results provide evidence for the involvement of Ac and ceramide in controlling infection by regulating red blood cell development.
酸性神经酰胺酶（Ac）是鞘脂代谢的一部分，负责降解神经酰胺。作为生物活性分子，神经酰胺参与了许多细胞过程的调节。然而，细胞内固有 Ac 活性和神经酰胺对疟原虫感染过程的影响仍不清楚。在这里，我们使用全身性神经酰胺水平升高的 Ac 缺陷小鼠来阐明内源性 Ac 活性在小鼠疟疾模型中的作用。有趣的是，Ac 的缺失导致寄生虫血症减轻，感染早期 T 细胞反应降低。从机制上讲，我们发现 Ac 缺陷小鼠的红细胞生成失调，网织红细胞数量减少，网织红细胞是疟原虫的首选宿主细胞。此外，我们证明在野生型小鼠中给予 Ac 抑制剂卡莫氟具有相似的疟原虫感染和红细胞生成作用。值得注意的是，在感染表现后进行卡莫氟的治疗性给药在降低寄生虫血症方面是有效的。因此，我们的结果为 Ac 和神经酰胺通过调节红细胞发育来控制疟原虫感染提供了证据。
