Genetic and biochemical modulation of sialic acid O-acetylation on group B Streptococcus: phenotypic and functional impact.
Group B Streptococcus (GBS) is an important human pathogen and a model system for studying the roles of bacterial glycosylation in host-microbe interactions. Sialic acid (Sia), expressed prominently in the GBS capsular polysaccharide (CPS), mimics mammalian cell surface Sia and can interact with host Sia-binding proteins to subvert immune clearance mechanisms. Our earlier work has shown that GBS partially O-acetylates CPS Sia residues and employs an intracellular O-acetylation/de-O-acetylation cycle to control the final level of this surface Sia modification. Here, we examine the effects of point mutations in the NeuD O-acetyltransferase and NeuA O-acetylesterase on specific glycosylation phenotypes of GBS, pinpointing an isogenic strain pair that differs dramatically in the degree of the O-acetyl modification (80% versus 5%) while still expressing comparable levels of overall sialylation. Using these strains, higher levels of O-acetylation were found to protect GBS CPS Sia against enzymatic removal by microbial sialidases and to impede engagement of human Siglec-9, but not to significantly alter the ability of GBS to restrict complement C3b deposition on its surface. Additional experiments demonstrated that pH-induced migration of the O-acetyl modification from the 7- to 9-carbon position had a substantial impact on GBS-Siglec-9 interactions, with 7-O-acetylation exhibiting the strongest interference. These studies show that both the degree and position of the GBS O-acetyl modification influence Sia-specific interactions relevant to the host-pathogen relationship. We conclude that native GBS likely expresses a phenotype of intermediate Sia O-acetylation to strike a balance between competing selective pressures present in the host environment.
Weiman
Shannon
S
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0687, USA.
Dahesh
Samira
S
Carlin
Aaron F
AF
Varki
Ajit
A
Nizet
Victor
V
Lewis
Amanda L
AL
D000107:Acetylation; D019158:N-Acetylneuraminic Acid / Q000737:chemistry* / Q000378:metabolism*; D010641:Phenotype; D013292:Streptococcus agalactiae / Q000145:classification / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*
D019158:N-Acetylneuraminic Acid