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Infection and Immunity, July 2007, p. 3406-3413, Vol. 75, No. 7
0019-9567/07/$08.00+0     doi:10.1128/IAI.00078-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Molecular Basis for Preferential Protective Efficacy of Antibodies Directed to the Poorly Acetylated Form of Staphylococcal Poly-N-Acetyl-ß-(1-6)-Glucosamine{triangledown}

Nuno Cerca,1,2 Kimberly K. Jefferson,1,3 Tomas Maira-Litrán,1 Danielle B. Pier,1 Casie Kelly-Quintos,1 Donald A. Goldmann,4 Joana Azeredo,2 and Gerald B. Pier1*

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts,1 Institute for Biotechnology and Bioengineering, Center for Biological Engineering, Universidade do Minho, Braga, Portugal,2 Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia,3 Children's Hospital, Harvard Medical School, Boston, Massachusetts4

Received 12 January 2007/ Returned for modification 28 February 2007/ Accepted 18 April 2007

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.

* Corresponding author. Mailing address: Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Ave., Boston, MA 02115. Phone: (617) 525-2269. Fax: (617) 525-2510. E-mail: gpier{at}channing.harvard.edu

{triangledown} Published ahead of print on 30 April 2007.

Editor: J. N. Weiser

Infection and Immunity, July 2007, p. 3406-3413, Vol. 75, No. 7
0019-9567/07/$08.00+0     doi:10.1128/IAI.00078-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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