Group B Streptococcus (GBS) causes invasive infections in human infants and immunocompromised individuals and is the leading cause of neonatal sepsis and meningitis. It is estimated that 20-30% of women of childbearing age are vaginal or rectal carriers of GBS.  While GBS colonization occurs asymptomatically, newborns can be infected with GBS in utero, due to ascending amniotic infection, or during delivery, by aspiration of contaminated vaginal fluids.  Pneumonia, sepsis and meningitis are potential complications of GBS infection, reflecting an array of bacterial virulence factors that act to impede phagocytic clearance and produce host tissue injury. It is estimated that approximately 3,600 neonates develop invasive GBS disease annually in the United States. According to the CDC, this represents an incidence of 0.4 per 1000 live births. Infants who survive GBS (19/20 according to CDC estimates) often exhibit learning disabilities, hearing or vision loss, or other neurological problems.


Mimicry of Host Sialic Acids

A major virulence factor of GBS is its sialylated capsular polysaccharide. Capsular sialic acids participate in suppression of the alternative pathway of complement and can also directly impair neutrophil bactericidal responses through interaction with the sialic acid-binding receptor Siglec-9.

We are interested in the roles played by capsule sialic acids during GBS colonization and infection.

Our genomic and biochemical investigations suggest that bacterial mimicry of host sialic acids may be a more common theme in bacterial immune evasion than previously recognized. 

Sialic Acid O-acetylation

We have shown that all GBS strains have low to moderate levels of sialic acid O-acetylation. The modification protects GBS sialic acids from hydrolysis by sialidases of gastrointestinal bacteria (see Figure 1). Although, the significance of this finding deserves further attention.

Site directed mutation of the sialic acid O-acetyl esterase generates a strain that is hyper-O-acetylated. Comparison of this strain to isogenic mutants with low levels of O-acetylation shows that this sialic acid modification impairs binding to host Siglec-9 and reduces virulence, but enhances resistance to most sialidases. 

Our recent studies of GBS in the urinary tract demonstrate that sialic acid residues of the capsule are also necessary for optimal fitness during localized GBS infections. 

The presence of GBS and its ability to precisely mimic host sialic acids also influences the severity of urinary tract infection (UTI) caused by E. coli, the most common cause of human UTI. 


Figure 1.  Isogenic GBS with high and low levels of O-acetylation were subjected to commercial sialidases cloned from several gut pathogens. GBS with higher levels of O-acetylation retained more sialic acid upon sialidase exposure. This data was published in Weiman et al, Glycobiology, 2009.

Figure 2.  Experiments with murine polymorphonuclear cells (PMNs) in vitro (LEFT) demonstrate that high levels of sialic acid O-acetylation impair the ability of GBS to 1) evade oxidative burst responses of PMNs, and 2) evade killing by PMNs. In the mouse urinary tract in vivo (RIGHT top), highly O-acetylated GBS are less virulent than their low O-acetylated counterparts (~5-fold difference). This defect in survival in the urinary tract was much more pronounced in competition experiments (see Kline et al, Infect. and Immun, 2011).

Papers on Group B Streptococcus

Kline, KA; Schwartz, DJ, Gilbert, NM; Hultgren, SJ; Lewis, AL. Immune Modulation by Group B Streptococcus Influences Host Susceptibility to Urinary Tract Infection by Uropathogenic Escherichia coli. Infect. Immun. 2012 Sept. 17. Epub ahead of print

Kline, K.A.; Schwartz, D.J.; Lewis, W.G.; Hultgren, S.J.; Lewis, A.L. Immune Activation and Suppression by Group B Streptococcus in a Murine Model of Urinary Tract Infection. Infect Immun. 2011 Sep;79(9):3588-95. http://www.ncbi.nlm.nih.gov/pubmed/21690238

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. Weiman_2010_Biochem.J.pdf

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. Carlin_2009_Blood.pdf

Pannaraj PS, Edwards MS, Ewing KT, Lewis AL, Rench MA, Baker CJ. 2009. Group B streptococcal conjugate vaccines elicit functional antibodies independent of strain O-acetylation. Vaccine.16;27(33):4452-6

Weiman S, Dahesh S, Carlin AF, Varki A, Nizet V, Lewis AL. 2009. Genetic and Biochemical Modulation of Sialic Acid O-Acetylation on Group B Streptococcus: Phenotypic and Functional Impact. Glycobiology. (11):1204 13. Weiman_2009_Glycobiology.pdf

Carlin, A.F.; Lewis, A.L.; Varki, A.; Nizet, V. 2007. Group B streptococcal capsular sialic acids interact with siglecs (immunoglobulin-like lectins) on human leukocytes. J Bacteriol. 189(4):1231 Carlin_2007_J.Bacteriol.pdf

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. Lewis_2007_JBC.pdf

Lewis, A.L.; Hensler, M.; Nizet, V; Varki, A. 2006. The group B streptococcal sialic acid O-acetyltransferase is encoded by neuD, a conserved component of bacterial sialic acid biosynthetic gene clusters. J Biol Chem. 281(16):11186. Lewis_2006_JBC.pdf

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. Lewis_2004_PNAS.pdf