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Infect. Immun. doi:10.1128/IAI.00078-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Molecular basis for preferential protective efficacy of antibodies directed to the poorly-acetylated form of staphylococcal poly-N-acetyl--(1-6)-glucosamine

Channing Laboratory, Department of Medicine, Brigham Women's Hospital, Harvard Medical School, Boston, USA, Centro de Engenharia Biológica, Universidade do Minho, Braga, Portugal, Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, USA, Children's Hospital, Harvard Medical School, Boston, USA

^* To whom correspondence should be addressed. Email: gpier{at}channing.harvard.edu.

	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 only bind to PNAG with high levels (>70%) of acetate. PNAG is synthesized by 4 proteins encoded within the intercellular adhesin (ica) locus-icaADBC. In S. epidermidis, icaB encodes a de-acetylase needed for surface retention of PNAG and optimal biofilm formation. In this study we confirmed that icaB plays a similar role in S. 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 to deacetylated PNAG (dPNAG), and had reduced survival capacity in a murine model of bacteremia. In contrast, an icaB over-expressing 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.

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