Role of sphingolipids in the host-pathogen interaction

Abstract

Fungal pathogens have been under the spotlight as their expanding geographic range combined with their potential harm to vulnerable populations turns them into increasingly threats to public health. Therefore, it is ultimately important to unveil the mechanisms associated with their infection process for further new treatment discovery. With this purpose, sphingolipid-based research has gained attention over the last years as these molecules have key properties that can regulate fungal pathogenicity. Here we discuss some of these properties as well as their role in fungal diseases, focusing on the subgroup of glycosphingolipids, as they represent promising molecules for drug discovery and for the development of fungal vaccines.

Keywords: Fungi; Glucosylceramide; Inositol phosphorylceramide; Pathogenicity; Sphingolipids.

Fig. 1.

The sphingolipid synthesis pathway. The initial steps occur in the endoplasmic reticulum (ER), with the condensation of palmitoyl-CoA and serine, forming 3-ketodihydrosphingosine (3-KDS), catalyzed by serine palmitoyltransferase. 3-KDS is then reduced to dihydrosphingosine (DHS) by 3-keto dihydrosphingosine reductase. DHS can be hydroxylated to generate phytosphingosine (PHS). DHS and PHS can be phosphorylated, forming DHS-1-P and PHS-1-P respectively, or acylated by distinct ceramide synthases, producing the pool of ceramides which will be used for the synthesis of neutral and acid sphingolipids. The transfer of inositol-phosphate to phytoceramide, catalyzed by inositol phosphorylceramide synthase (Ipc1) in the Golgi, leads to the synthesis of inositol phosphorylceramide (IPC). Finally, IPCs are mannosylated into mannosyl-inositol phosphorylceramides (MIPC). The final step of the neutral sphingolipid synthesis consists of the addition of a glucose moiety to Δ8-C9,Me-Cer and is catalyzed by glucosylceramide (GlcCer) synthase (Gcs1) in the Golgi.

Fig. 2.

Role of glycosphingolipids in fungal virulence. Fungal cells, containing both IPCs and Δ8-C9,Me-Cer are able to evade immune response, especially in immunocompromised individuals (Left panel). Once the synthesis of either GlcCer or IPC is compromised, fungal ability to infect the host cells is lost or drastically reduced, leading to fungal capture by immune cells such as macrophages (Right panel).