Sialic Acids as Receptors for Pathogens

Abstract

Carbohydrates have long been known to mediate intracellular interactions, whether within one organism or between different organisms. Sialic acids (Sias) are carbohydrates that usually occupy the terminal positions in longer carbohydrate chains, which makes them common recognition targets mediating these interactions. In this review, we summarize the knowledge about animal disease-causing agents such as viruses, bacteria and protozoa (including the malaria parasite Plasmodium falciparum) in which Sias play a role in infection biology. While Sias may promote binding of, e.g., influenza viruses and SV40, they act as decoys for betacoronaviruses. The presence of two common forms of Sias, Neu5Ac and Neu5Gc, is species-specific, and in humans, the enzyme converting Neu5Ac to Neu5Gc (CMAH, CMP-Neu5Ac hydroxylase) is lost, most likely due to adaptation to pathogen regimes; we discuss the research about the influence of malaria on this trait. In addition, we present data suggesting the CMAH gene was probably present in the ancestor of animals, shedding light on its glycobiology. We predict that a better understanding of the role of Sias in disease vectors would lead to more effective clinical interventions.

Keywords: CMAH gene; phylogenetic tree; receptors for pathogens; sialic acids.

Figure 1

Structure of sialic acids: (a) Neuraminic acid, (b) 2-keto-deoxynonulosonic acid, (c) N-acetylneuraminic acid, (d) N-glycolylneuraminic acid and (e) N-acetyl-9-O-acetylneuraminic acid.

Figure 2

Single protein maximum likelihood tree of CMAH protein sequences from various species. Sponge CMAH proteins form a clade and are grouped together with other metazoan sequences. Sequences were aligned using MUSCLE [29], trimmed in Geneious 8.1.9 (BioMatters, Ltd., Auckland, NZ) [30] and the tree was made in IQTree v2.1.2 [31] with the substitution model (LG+I+G4) selected using ModelFinder [32]. Nonparametric bootstrap branch supports are shown next to the nodes. As evident from the non-basal position of cnidarians, single protein trees only approximate true phylogenetic relationships.

Figure 3

Organization of the CMAH gene. The human gene lacks coding exon 3 in comparison to the mouse and the chimpanzee genes. The ticks show exons that are putatively still functional, and the crosses denote exons that were damaged in the human pseudogene, resulting in either premature STOP codons or inactivating mutations in the protein product. The exons are drawn to scale relative to each other, and the introns were rescaled to the same length.

Figure 4

The F2-binding pocket of the PfEBA-140 ligand with the bound N-acetylneuraminic acid. The amino acid residues and backbone atoms involved in sugar binding are shown (according to [205], modified). Figure made in ccp4mg [208] using PDB ID 4JNO.