Ceramide and Related Molecules in Viral Infections

Abstract

Ceramide is a lipid messenger at the heart of sphingolipid metabolism. In concert with its metabolizing enzymes, particularly sphingomyelinases, it has key roles in regulating the physical properties of biological membranes, including the formation of membrane microdomains. Thus, ceramide and its related molecules have been attributed significant roles in nearly all steps of the viral life cycle: they may serve directly as receptors or co-receptors for viral entry, form microdomains that cluster entry receptors and/or enable them to adopt the required conformation or regulate their cell surface expression. Sphingolipids can regulate all forms of viral uptake, often through sphingomyelinase activation, and mediate endosomal escape and intracellular trafficking. Ceramide can be key for the formation of viral replication sites. Sphingomyelinases often mediate the release of new virions from infected cells. Moreover, sphingolipids can contribute to viral-induced apoptosis and morbidity in viral diseases, as well as virus immune evasion. Alpha-galactosylceramide, in particular, also plays a significant role in immune modulation in response to viral infections. This review will discuss the roles of ceramide and its related molecules in the different steps of the viral life cycle. We will also discuss how novel strategies could exploit these for therapeutic benefit.

Keywords: HIV-1; IAV; SARS-CoV-2; acid sphingomyelinase; antiviral therapies; ceramide; immunomodulation; lipid-rafts; sphingolipids; viral infection; α-galactosylceramide.

Figure 1

Sphingolipid structures. Ceramide consists of a sphingosine backbone (black) and one of several fatty acids (red), which differ in chain length and degree of saturation. Thus, the term “ceramide” actually describes a whole class of molecules. The addition of certain, invariant polar head groups (blue) results in sphingolipid classes that only vary in their underlying ceramide, whereas the addition of variable sugar groups (green) results in different glycosphingolipids. These are the most complex group, as the type and linkage of sugar residues added differ in addition to the fatty acid chain.

Figure 2

Sphingolipid metabolism. Ceramide is the central hub of sphingolipid metabolism. De novo synthesis (blue) starts with palmitoyl CoA, and the salvage pathway starts with conversion to sphingosine and ends with a fatty aldehyde and ethanolamine-phosphate (green). The synthesis of glycosphingolipids starts with the formation of glucosylceramide (purple). Other key pathways are phosphorylation to ceramide-1-phosphate (blue-gray), conversion to sphingomyelin (orange) and glycosylation to α-galactosylceramide and sulfatide (yellow). Inhibitors of ceramide-metabolizing enzymes are shown in red. Cer: ceramide; GlcCer: glucosylceramide; S1P: sphingosine 1-phosphate; SM: sphingomyelin.

Figure 3

Role of sphingolipids in ebola-, influenza- and Zika virus replication. The life cycles of ebola virus (EBOV), influenza A virus (IAV) and Zika virus (ZIKV) show some of the diversity of viral replication and summarize key steps in which sphingolipids play a role in the viral life cycle. Supporting roles, i.e., the virus using sphingolipid-domains for cell entry or the formation of replication sites, are highlighted in green. Inhibitory roles are marked in red. ASM: acid sphingomyelinase, NSM: natural sphingomyelinase, SM: sphingomyelin, SphK1: sphingosine 1-kinase.