How bacteria utilize sialic acid during interactions with the host: snip, snatch, dispatch, match and attach

Abstract

N -glycolylneuraminic acid (Neu5Gc), and its precursor N-acetylneuraminic acid (Neu5Ac), commonly referred to as sialic acids, are two of the most common glycans found in mammals. Humans carry a mutation in the enzyme that converts Neu5Ac into Neu5Gc, and as such, expression of Neu5Ac can be thought of as a 'human specific' trait. Bacteria can utilize sialic acids as a carbon and energy source and have evolved multiple ways to take up sialic acids. In order to generate free sialic acid, many bacteria produce sialidases that cleave sialic acid residues from complex glycan structures. In addition, sialidases allow escape from innate immune mechanisms, and can synergize with other virulence factors such as toxins. Human-adapted pathogens have evolved a preference for Neu5Ac, with many bacterial adhesins, and major classes of toxin, specifically recognizing Neu5Ac containing glycans as receptors. The preference of human-adapted pathogens for Neu5Ac also occurs during biosynthesis of surface structures such as lipo-oligosaccharide (LOS), lipo-polysaccharide (LPS) and polysaccharide capsules, subverting the human host immune system by mimicking the host. This review aims to provide an update on the advances made in understanding the role of sialic acid in bacteria-host interactions made in the last 5-10 years, and put these findings into context by highlighting key historical discoveries. We provide a particular focus on 'molecular mimicry' and incorporation of sialic acid onto the bacterial outer-surface, and the role of sialic acid as a receptor for bacterial adhesins and toxins.

Keywords: N-acetylneuraminic acid; N-glycolylneuraminic acid; Neu5Ac; Neu5GC; adherence; adhesin; bacterial pathogen; molecular mimicry; sialic acid.

Fig. 1.

Structures of N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), and the graphical representation of these glycans as per SNFG guidelines.

Fig. 2.

The role of sialic acid in the pathobiology of (a) Neisseria gonorrhoeae and (b) nontypeable Haemophilus influenzae (NTHi). (a) The role of sialic acid in serum resistance was first described in Neisseria gonorrhoeae , with Neu5Ac-CMP the host-acquired molecule, which resulted in this resistance. Addition of Neu5Ac to the LOS of N. gonorrhoeae is catalysed by the enzyme Lst, with Neu5Ac-CMP transported by an as yet unidentified transporter. Whether Lst acts extracellularly, or in the cytoplasm, is also unclear. Incorporation of Neu5Ac into LOS also allows ‘molecular mimicry’ of the host by adding the human specific sugar to a key bacterial surface feature, masking the bacteria from the immune response. (b) NTHi is one of the best studied bacterial pathogens as regards use of sialic acid during pathobiology, and displays several examples of evolution of host-adaptation. Whist NTHi can take up both Neu5Ac and Neu5Gc with equal affinity via NanC and the TRAP transporter SiaPT, NTHi shows a marked preference for decorating LOS with Neu5Ac, with the bias being at activation of sialic acids for addition to LOS; the enzyme SiaB, which adds a CMP to sialic acid, shows 4000-fold higher affinity for Neu5Ac over Neu5Gc. In addition, the major NTHi adhesins HMW1/2 and Hia have both evolved to interact specifically with sialic acid containing receptors in the human airway, despite never being found in the same strains of NTHi. HMW 1 shows equal affinity for both α2,3-sialyllactosamine (2–3 SLN) containing either Neu5Ac or Neu5Gc, whereas HMW2 shows high affinity for α2,6-sialyllactosamine (2–6 SLN) containing Neu5Ac. Hia shows a marked preference for 2–6 SLN containing Neu5Ac, but also binds 2–6 SLN containing Neu5Gc, and 2–3 SLN. This convergent evolution of different adhesins for the same receptor means that all NTHi strains can colonize the human airway. The weight of the dashed line indicates specificity for particular sialic acid-containing structures.

Fig. 3.

Two major groups of bacterial toxins have evolved to specifically recognize sialic acid containing glycans. The CDCs (cholesterol dependent cytolysis), produced by Gram-positive bacteria, and the AB₅ toxins, made by Gram-negative bacteria, both utilize host glycans as cellular receptors, with many specifically recognizing sialic acid containing glycan structures. Where available, the K _D (dissociation constant) is shown for the glycan structure with the highest affinity binding to each toxin. The action of Ctx, produced by Vibrio cholerae , requires the action of the neuraminidase VcN to cleave Neu5Ac in order to expose the underlying glycan structure, which is the preferred receptor. Host-evolution is evident for the AB₅ toxins, produced by Shiga-toxin producing E. coli (STEC; SubAB), and Salmonella spp. SubAB binds both Neu5Ac and Neu5Gc containing glycan structures, with a preference for Neu5Gc containing structures, demonstrating the broad mammalian host range of STEC; Typhoid toxin (PltAB), produced by the human-restricted pathogen Salmonella Typhi, binds Neu5Ac linked via an α2,6- or and α2,3-linkage, whereas Javiana toxin, produced by Salmonella Javiana, shows a marked preference for α2,3-linked Neu5Ac. These differences in receptor specificity strongly influence disease severity resulting from infections by these organisms.