Animal and human antibodies to distinct Staphylococcus aureus antigens mutually neutralize opsonic killing and protection in mice
David Skurnik, … , Jean C. Lee, Gerald B. Pier
David Skurnik, … , Jean C. Lee, Gerald B. Pier
Published August 25, 2010
Citation Information: J Clin Invest. 2010;120(9):3220-3233. https://doi.org/10.1172/JCI42748.
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Research Article

Animal and human antibodies to distinct Staphylococcus aureus antigens mutually neutralize opsonic killing and protection in mice

Abstract

New prophylactic approaches are needed to control infection with the Gram-positive bacterium Staphylococcus aureus, which is a major cause of nosocomial and community-acquired infections. To develop these, greater understanding of protective immunity against S. aureus infection is needed. Human immunity to extracellular Gram-positive bacterial pathogens is primarily mediated by opsonic killing (OPK) via antibodies specific for surface polysaccharides. S. aureus expresses two such antigens, capsular polysaccharide (CP) and poly-N-acetyl glucosamine (PNAG). Here, we have shown that immunization-induced polyclonal animal antisera and monoclonal antibodies specific for either CP or PNAG antigens have excellent in vitro OPK activity in human blood but that when mixed together they show potent interference in OPK activity. In addition, reductions in antibody binding to the bacterial surface, complement deposition, and passive protection were seen in two mouse models of S. aureus infection. Electron microscopy, isothermal calorimetry, and surface plasmon resonance indicated that antibodies to CP and PNAG bound together via an apparent idiotype–anti-idiotype interaction. This interaction was also found in sera from humans with S. aureus bacteremia. These findings suggest that the lack of effective immunity to S. aureus infections in humans could be due, in part, to interference in OPK when antibodies to CP and PNAG antigens are both present. This information could be used to better design S. aureus vaccine components.

Authors

David Skurnik, Massimo Merighi, Martha Grout, Mihaela Gadjeva, Tomas Maira-Litran, Maria Ericsson, Donald A. Goldmann, Susan S. Huang, Rupak Datta, Jean C. Lee, Gerald B. Pier

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Figure 8

Examples of the patterns of OPKA against S. aureus PS80 (CP8) or Newman (CP5) in sera from patients with S. aureus bacteremia.

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Examples of the patterns of OPKA against S. aureus PS80 (CP8) or Newman ...
(A) Serum without OPKA (activity, <30%). (B) CP8-specific OPKA inhibited by addition of CP8 antigen (25 μg/ml). (C) PNAG-specific OPKA inhibited by addition of PNAG antigen (50 μg/ml). (D) PNAG- and CP8-specific OPKA in monospecific and combined antisera, showing no effect from combining monospecific samples. (E) PNAG- and CP8-specific OPKA with augmentation by combining monospecific samples. (F) PNAG- and CP8-specific OPKA, with loss of OPKA when combined together. (G) PNAG- and CP5-specific OPKA, with loss of OPKA when combined together. (H) PNAG- and CP8-specific OPKA in adsorbed, monospecific samples, with loss of OPKA when recombined together, an effect that is unchanged after adsorption by the S. aureus MN8Δcap + Δica strain that leaves both antibodies in the serum. OPKA is restored when specific antigen to either PNAG or CP8 is added to the recombined, previously monospecific, adsorbed samples. (I) PNAG- and CP8-specific OPKA in adsorbed, monospecific samples, with loss of OPKA when combined together and with no OPKA in the serum after adsorption by the S. aureus MN8Δcap + Δica strain and with OPKA restored when specific antigen to PNAG but not CP8 is added to the recombined, previously monospecific, adsorbed samples. Bars represent means of quadruplicate counts with SEM less than 10% (not shown). Controls lacking PMNs all showed less than 10% OPKA (not shown).