Significance of sialic acid in Klebsiella pneumoniae K1 capsules

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In this issue of virulence, Lee and colleagues1 describe the physical presence and pathophysiologic importance of sialic acid within the polysaccharide exocapsule of Klebsiella pneumoniae. Klebsiella pneumoniae serotype K1 or K2 are the primary pathogens found in primary liver abscess, a common and potentially life threatening infection found worldwide but particularly in adult patients in Asia. The virulence determinants which give this special ability of Klebsiella pneumoniae capsular serotype K1/K2 are not fully understood, but the unique features of the capsule polysaccharide itself likely contributes to the capacity of this organism to evade host defense mechanisms and to proliferate within the host.2 In the current study1 the importance of sialic acid within the polysaccharide capsule material of Klebsiella pneumoniae is well demonstrated in this set of experiments. The investigators find abundant quantities of sialic acid which differs from the capsular polysaccharides of other Klebsiella serotypes. Removing sialic acids by sialidase enzymes reduce the intrinsic resistance of the K. pneumoniae K1 to neutrophil phagocytosis. Siglec-9 (sialic acid-binding immunoglobulin-like lectin-9) readily binds to sialic acids within the capsular polysaccharide of K. pneumoniae K1 and alters neutrophil phagocytic activity.3 Sialic acids are ubiquitous monosaccharide constituents of numerous glycopolymers that are widely expressed along the cell surface of human tissues and selected microbial pathogens.4 Sialic acid, also known as N-acetyl-neuraminic acid, often decorates the terminal branches of N-linked glycans and O-glycans found within the glycocalyx lining of eukaryotic cell surfaces. The basic structure of sialic acid is a 9 carbon, acidic, α-keto monosaccharide featuring a C6-linked tri-hydroxyl three carbon side chain and a C1-linked carboxyl group giving it a strong electronegative charge. At least 50 members of the sialic acid family are now known, all of which share this common core structure.4 When sialic acids are linked together as polyamers, its dense negative charge provides a highly viscous material that could easily contribute to the hypermucoviscosity phenotype observed in clinical isolates of Klebsiella pneumoniae from liver abscess material. Capping of other glycans with sialic acid residues can serve multiple functions for human cells. They can sterically inhibit recognition sites for pathogens thereby interfering with high-affinity binding to surface glycans. Highly pathogenic strains of Streptococcus pneumoniae express a sialidase to remove sialic acid from the respiratory epithelial glycolipids allowing it to reach to its preferred binding motif, the disaccharide structure N-acetyl-glucosamine-β-(1,4)-galactose.5 Pneumococci generate this sialidase as a virulence factor allowing it to bind and efficiently colonize the respiratory epithelium. Terminal sialic acid residues serve similar functions as masking surface binding sites and surface epitopes. Sialic acid polymers expressed in K. pneumoniae K1 capsules likely contribute to its increased viscosity, its direct anti-phagocytic activity, and indirectly inhibit neutrophil phagocytic activity through siglec-9 binding to sialic acid which sends inhibitory signals to neutrophils.1 Another possible pathogen advantage of sialic acid within its capsular polysaccharides is its ability to impair complement activation by binding to the complement inhibitory component factor H (also known as β-1 H). This complement evasion strategy is employed by E. coli K1 in which this capsular polysaccharide is covered with O-acetylated sialic acid. Sialic avidly binds factor H preventing C3bi binding to the bacterial surface by the alternative complement pathway.6 It’s likely that the glyco-chemistry of the Klebsiella spp. polysaccharide capsule is only part of the overall virulence capacity of K. pneumoniae K1. Nonetheless, the work of Lee and colleagues does provide a novel insight into how this pathogen succeeds in causing liver abscesses. Therapeutic efforts could conceivably target sialic acid expression on this mucoid genotype of K. pneumoniae with sialidases or other inhibitors of sialic acid synthesis. More research is needed to understand this pathogen, its proclivity to develop primary liver abscesses, and methods to prevent liver abscess. The findings presented in this current investigation brings us one step closer to achieving this goal.1