Multifarious roles of sialic acids in immunity

Abstract

Sialic acids are a diverse family of monosaccharides widely expressed on all cell surfaces of vertebrates and so-called "higher" invertebrates, and on certain bacteria that interact with vertebrates. This overview surveys examples of biological roles of sialic acids in immunity, with emphasis on an evolutionary perspective. Given the breadth of the subject, the treatment of individual topics is brief. Subjects discussed include biophysical effects regulation of factor H; modulation of leukocyte trafficking via selectins; Siglecs in immune cell activation; sialic acids as ligands for microbes; impact of microbial and endogenous sialidases on immune cell responses; pathogen molecular mimicry of host sialic acids; Siglec recognition of sialylated pathogens; bacteriophage recognition of microbial sialic acids; polysialic acid modulation of immune cells; sialic acids as pathogen decoys or biological masks; modulation of immunity by sialic acid O-acetylation; sialic acids as antigens and xeno-autoantigens; antisialoglycan antibodies in reproductive incompatibility; and sialic-acid-based blood groups.

Figure 1

Examples of roles of sialic acids in immunity. Sialic acids are shown as pink diamonds. See the text for details. (A) Neu5Ac, the most common sialic acid in mammals. These acidic sugars share a 9-carbon backbone and can be modified in many ways. (B) The high density of terminal sialic acids on the glycocalyx of vertebrate cells imparts negative charge and hydrophilicity to cell surfaces, altering biophysical properties.(C) Factor H binds cell surface Sias, protecting cell surfaces from the alternative complement pathway.(D) Intrinsic Sia-binding molecules such as selectins on endothelia, leukocytes, and platelets initiate leukocyte rolling on endothelial surfaces, a key initial step for leukocyte extravasation. (E) Intrinsic Sia-binding Siglec molecules on immune cells detect sialylated ligands and can inhibit immune cell activation. There are also activatory Siglecs. (F) Host Sias are frequently exploited as attachment sites (“receptors”) by pathogens including protozoa, viruses, bacteria, and toxins. (G) Microbial sialidases can help pathogens to expose underlying glycan binding sites, to avoid sialylated decoys (see below), and and/or provide Sias as food sources. The loss of SAMPs from cells may then be used by host immune cells to react to pathogens, and/or to clear away desialylated cells or glycoproteins. (H) Endogenous sialidases such as Neu1 can modulate immune cell function by modulating receptor clustering, possibly by exposing underlying galactose residues and facilitating galectin mediated cross-linking of surface molecules. (I) Microbial mimicry of host Sias allows manipulation of host immune response by engaging inhibitory Siglecs, inhibiting complement via factor H binding, and reducing the opportunity of the host to form antibodies. (J) Microbial synthesis of Sia-like molecules, such as legionaminic acid and pseudaminic acid stabilizes fimbriae.

Figure 2

More examples of roles of sialic acids in immunity. Sialic acids are shown as pink diamonds. See key in Figure 1, and the text for details. (A) Siglec-1 (sialoadhesin) expressed on macrophages recognizes Sias in patterns commonly found on microbial pathogens and facilitates phagocytosis. Siglec-1 may also mediate immune cell interactions with one another. Some viruses exploit Siglec-1 binding to gain access to host cells. (B) Certain bacteriophages use Sias on their microbial hosts as “receptors” for invasion. (C) Polysialic acid on immune molecules such as neuropilin on dendritic cells modulates interactions with T cells. (D) Sia-rich secretions on host epithelia can act as decoys for Sia-binding microbes. (E) Sia-covered erythrocytes and Sia-rich plasma proteins can act as “viral traps.” (F) Sias act as biological masks by blocking interactions between intrinsic receptors and underlying glycan structures. (G) Sias on potentially antigenic glycoconjugates prevent the formation of antibodies to “cryptoantigens.” Less commonly, Sias can be autoantigens. (H) Non-self Sias can be metabolically incorporated from dietary sources and become “xeno-autoantigens,” targeted by intrinsic anti-Sia antibodies. (I) Female genital tract reactions to non-self Sia on sperm can lead to reproductive incompatibility. (J) Some mammals, such as cats, have blood groups defined by Sia-containing glycolipids. (K) O-acetylation of Sias can block Sia recognition by intrinsic lectins like Siglecs, and modulate microbial lectin interactions, in a positive or negative fashion. (L) Alpha-2–6 sialylation of IgG-Fc region N-glycans can change the effects of IgG antibodies from activating to inhibitory.