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 4

Specificity of the interference resulting from combined antisera to CP and PNAG antigens in protection against S. aureus skin abscesses in mice.

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Specificity of the interference resulting from combined antisera to CP a...
(A) Effect on levels of S. aureus LAC in skin abscesses after adsorption (ads) of rabbit antisera to PNAG, CP8, or NRS with S. aureus MN8 Δica to remove all antibodies except those to PNAG or adsorption with S. aureus MN8 Δcap8 to remove antibodies to PNAG. (B) Reduction in CFU/abscess of S. aureus PS80 by antibody to PNAG (compared with NRS, black lines) is lost when this antibody is combined with antibody to CP8 (blue lines). Adsorption of the antibody to CP8 with S. aureus MN8 Δcap8 does not restore protective efficacy (red lines), but adsorption with S. aureus MN8 Δica to remove antibody to CP8 relieves interference (green lines). (C) Reduction in CFU/abscess of S. aureus PS80 by antibody to CP8 (compared with NRS, black lines) is lost when this antibody is combined with antibody to PNAG (blue). Adsorption of the antibody to PNAG with S. aureus MN8 Δica does not restore protective efficacy (red), but adsorption with S. aureus MN8 Δcap8 to remove antibody to PNAG relieves interference (green). Each point represents an individual mouse; lines represent medians. P = 0.01 for overall Kruskal-Wallis ANOVA. P values for pairwise comparisons shown in the graphs were determined by the Dunn procedure.