title: Molecular basis for preferential protective efficacy of antibodies directed to the poorly acetylated form of staphylococcal poly-N-acetyl-beta-(1-6)-glucosamine.
abstract: Poly-N-acetyl-glucosamine (PNAG) is a staphylococcal surface polysaccharide influencing biofilm formation that is also under investigation for its vaccine potential. Antibodies that bind to PNAG with either low (<15%) or high (>90%) levels of acetate are superior at opsonic and protective activity compared with antibodies that bind to PNAG with only high levels (>70%) of acetate. PNAG is synthesized by four proteins encoded within the intercellular adhesin (ica) locus icaADBC. In Staphylococcus epidermidis, icaB encodes a deacetylase needed for the surface retention of PNAG and optimal biofilm formation. In this study, we confirmed that icaB plays a similar role in Staphylococcus aureus and found that an icaB mutant of S. aureus expressed significantly less surface-associated PNAG, was highly susceptible to antibody-independent opsonic killing that could not be enhanced with antibody raised against deacetylated PNAG (dPNAG), and had reduced survival capacity in a murine model of bacteremia. In contrast, an icaB-overexpressing strain produced primarily surface-associated PNAG, was more susceptible to opsonophagocytosis with antibody to dPNAG, and had increased survival in a murine bacteremia model. The highly acetylated secreted PNAG was more effective at blocking opsonic killing mediated by a human monoclonal antibody (mAb) to native PNAG than it was at blocking killing mediated by a human mAb to dPNAG, which by itself was a more effective opsonin. Retention of dPNAG on the surface of S. aureus is key to increased survival during bacteremia and also provides a molecular mechanism explaining the superior opsonic and protective activity of antibody to dPNAG.
authors.affiliation: Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Nuno
authors.initials: N
authors.lastname: Cerca
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Jefferson
authors.forename: Tomas
authors.initials: T
authors.lastname: Maira-Litrán
authors.forename: Danielle B
authors.initials: DB
authors.lastname: Pier
authors.forename: Casie
authors.initials: C
authors.lastname: Kelly-Quintos
authors.forename: Donald A
authors.initials: DA
authors.lastname: Goldmann
authors.forename: Joana
authors.initials: J
authors.lastname: Azeredo
authors.forename: Gerald B
authors.initials: GB
authors.lastname: Pier
mesh_terms: D000117:Acetylglucosamine / Q000276:immunology* / Q000378:metabolism; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology*; D016470:Bacteremia / Q000276:immunology / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control*; D018441:Biofilms / Q000254:growth & development; D005260:Female; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D009895:Opsonin Proteins; D010587:Phagocytosis; D011135:Polysaccharides, Bacterial / Q000737:chemistry; D013203:Staphylococcal Infections / Q000276:immunology / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control; D013211:Staphylococcus aureus / Q000235:genetics / Q000254:growth & development / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D009895:Opsonin Proteins; D011135:Polysaccharides, Bacterial; C113831:poly-N-acetyl glucosamine; D000581:Amidohydrolases; C497363:poly-N-acetylglucosamine deacetylase; D000117:Acetylglucosamine