Sialic acids in Biology and Disease

Role of capsular polysaccharide sialic acids and O-acetylation in urogenital and systemic infections caused by Group B Streptococcus

Group B Streptococcus (GBS) is the leading cause of sepsis and meningitis in newborns. Infants can become infected with GBS after exposure to the colonized maternal reproductive tract. My research in this area began more than a decade ago with engineering multiple steps in the biosynthetic pathway that controls capsular polysaccharide expression and modification in GBS. I demonstrated that sialic acids on the capsule of GBS are modified by O-acetylation. This modification had been missed in >30 years of study on the GBS capsule as a vaccine target. We also demonstrated a new mechanism of GBS sialic acid mimicry, showing that GBS engages Siglec-9 expressed on human neutrophils, ultimately dampening neutrophil bactericidal functions. I went on to show that at high levels, O-acetylation reduces optimal mimicry of sialic acids, impairing interaction with Siglec-9, and leading to a reduced ability to evade neutrophil bactericidal responses, important for both systemic infection and localized urogenital infection.

  1. Lewis, A.L.; Nizet, V.; Varki. A.  2004. Discovery and Characterization of Sialic Acid O-Acetylation in Group B Streptococcus. Proc. Nat. Acad. Sci. U.S.A. 101(30): 11123-11128. PMID: 15263085. PMCID: PMC503750

  2. Lewis, A.L.; Cao, H.; Patel, S.K.; Diaz, S.; Ryan, W.; Carlin, A.F.; Thon, V.; Lewis, W.G.; Varki, A.; Chen, X.; Nizet, V. 2007. NeuA sialic acid O-acetylesterase activity modulates O-acetylation of capsular polysaccharide in Group B Streptococcus. J. Biol. Chem. 282(38):27562-71. PMID: 17646166 PMCID: PMC2588433

  3. Carlin, A.; Uchiyama, S.; Chang, Y.; Lewis, A.L.; Nizet, V.; Varki, A. 2009. Molecular Mimicry of Host Sialylated Glycans Allows a Bacterial Pathogen to Engage Neutrophil Siglec-9 and Dampen the Innate Immune Response. Blood. 113(14):3333-6. PMID: 19196661. PMCID: PMC2665898

  4. Weiman S, Uchiyama S, Lin FY, Chaffin D, Varki A, Nizet V, Lewis AL. 2010. O-Acetylation of Sialic Acid on Group B Streptococcus Inhibits Neutrophil Suppression and Virulence. Biochem J. 428(2):163-8. PMCID: PMC3640289

Evolution and function of sialic acids and related molecules

Sialic acids are found on all mammalian cells, and mimicry of these molecules is an important virulence factor for many bacteria. We demonstrated that de novo sialic acid synthesis pathways have evolved independently multiple times in bacteria and provided evidence for several possible new instances of sialic acid mimicry among bacterial pathogens. We have gone on to test some of the predictions of sialic acid mimicry in new contexts and to define the pathogenic potential of sialic acid-like molecules during bacterial infection.

 

  1. Lewis, A.L.; Desa, N.; Hansen, E.E.; Knirel, Y.; Gordon, J.; Gagneux, P.; Nizet, V.; Varki, A. 2009. Innovations in Host and Microbial Sialic Acid Biosynthesis Revealed by Phylogenomic Prediction of Nonulosonic Acid Structure. Proc Natl Acad Sci U S A. 106(32):13552-7. PMID: 19666579. PMCID: PMC2726416

  2. RicaldiJN; Matthias, MA; Vinetz, JM; Lewis, AL. 2012 Expression of Sialic Acids and other Nonulosonic Acids in Leptospira. BMC Microbiol. 12 (1):161. PMID: 22853805. PMCID: PMC3438082

  3. Lewis AL, Robinson LS, Agarwal K, Lewis WG. Discovery and Characterization of de novo Sialic Acid Biosynthesis in the Phylum Fusobacterium. Glycobiology. 2016; 26(10):1107-1119. PMID: 27613803. PMCID: PMC5072148

  4. Lubin, JB, Lewis, WG, Gilbert, NM, Almagro-Moreno, S, Boyd, EF, Lewis, AL. Host-like carbohydrates promote bloodstream survival of Vibrio vulnificus in vivo. Infect Immun. 2015 Aug;83(8):3126-36. Epub 2015 May 26. PMID: 26015477. PMCID: PMC4496609

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Transmission electron micrograph of Fusobacterium nucelatum.