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Review
. 2019 Dec 6:7:324.
doi: 10.3389/fcell.2019.00324. eCollection 2019.

Glycosphingolipids and Infection. Potential New Therapeutic Avenues

Johannes M F G Aerts  1 , M Artola  1 , M van Eijk  1 , M J Ferraz  1 , R G Boot  1
Affiliations
Review

Glycosphingolipids and Infection. Potential New Therapeutic Avenues

Johannes M F G Aerts et al. Front Cell Dev Biol. .

Abstract

Glycosphingolipids (GSLs), the main topic of this review, are a subclass of sphingolipids. With their glycans exposed to the extracellular space, glycosphingolipids are ubiquitous components of the plasma membrane of cells. GSLs are implicated in a variety of biological processes including specific infections. Several pathogens use GSLs at the surface of host cells as binding receptors. In addition, lipid-rafts in the plasma membrane of host cells may act as platform for signaling the presence of pathogens. Relatively common in man are inherited deficiencies in lysosomal glycosidases involved in the turnover of GSLs. The associated storage disorders (glycosphingolipidoses) show lysosomal accumulation of substrate(s) of the deficient enzyme. In recent years compounds have been identified that allow modulation of GSLs levels in cells. Some of these agents are well tolerated and already used to treat lysosomal glycosphingolipidoses. This review summarizes present knowledge on the role of GSLs in infection and subsequent immune response. It concludes with the thought to apply glycosphingolipid-lowering agents to prevent and/or combat infections.

Keywords: glucosylceramide; glycosidase; glycosphingolipid; glycosyltransferase; infection; lysosome.

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Figures

FIGURE 1
FIGURE 1
Structure and synthesis of glycosphingolipids. (A) Synthesis of complex glycosphingolipids (GSLs) from the simple building blocks L-serine, fatty acyl-CoA, and UDP-sugars. (B) General structure of glycosphingolipid: indicated are the major globo-, isoglobo-, ganglio-, lacto-, and neolacto-series core structures.
FIGURE 2
FIGURE 2
Lipid rafts and other functions of glycosphingolipids. (A) Glycosphingolipids are essential components of lipid rafts where signaling events occur in response to extracellular triggers. Excessive GSLs (GM3) may interfere with signaling. (B) GSLs may interact with toxins, bacteria and trans-cellular lectins and carbohydrates. Adapted from Feingold and Elias (2014).
FIGURE 3
FIGURE 3
Examples of direct interactions of glycosphingolipids with pathogens and toxins.
FIGURE 4
FIGURE 4
Metabolism of glycosphingolipids. (A) Lysosomal degradation by glycosidases assisted by activator proteins. Indicated are common lysosomal storage disorders stemming from inherited defects in lysosomal hydrolases. (B) Therapeutic reduction of glycosphingolipids by inhibition of glucosylceramide synthase (GCS). Shown are two clinically registered GCS inhibitors (Miglustat, N-butyl-deoxynojirimycin) and Eliglustat (N-[(1R,2R)-1-(2,3-Dihydro-1,4-benzodioxin-6-yl) -1-hydroxy-3-(1-pyrrolidinyl)-2-propanyl]octanamide), and AMP-DNM (N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin) commonly employed in research.
See this image and copyright information in PMC

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