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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.

SUBMITTER: Skurnik D

PROVIDER: S-EPMC2929724 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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

Skurnik David D Merighi Massimo M Grout Martha M Gadjeva Mihaela M Maira-Litran Tomas T Ericsson Maria M Goldmann Donald A DA Huang Susan S SS Datta Rupak R Lee Jean C JC Pier Gerald B GB

The Journal of clinical investigation 20100825 9

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, capsu ...[more]

PMID: 20739753

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Project description:Aminoglycoside antibiotics rely on the proton motive force to enter the bacterial cell, and facultative anaerobes like Staphylococcus aureus can shift energy generation from respiration to fermentation, becoming tolerant of aminoglycosides. Following this metabolic shift, high concentrations of aminoglycosides are required to eradicate S. aureus infections, which endangers the host due to the toxicity of aminoglycosides. Membrane-disrupting molecules prevent aminoglycoside tolerance in S. aureus by facilitating passive entry of the drug through the membrane. Polyunsaturated fatty acids (PUFAs) increase membrane permeability when incorporated into S. aureus. Here, we report that the abundant host-derived PUFA arachidonic acid increases the susceptibility of S. aureus to aminoglycosides, decreasing the aminoglycoside concentration needed to kill S. aureus. We demonstrate that PUFAs and aminoglycosides synergize to kill multiple strains of S. aureus, including both methicillin-resistant and -susceptible S. aureus. We also present data showing that PUFAs and aminoglycosides effectively kill S. aureus small colony variants, strains that are particularly recalcitrant to killing by many antibiotics. We conclude that cotreatment with PUFAs, which are molecules with low host toxicity, and aminoglycosides decreases the aminoglycoside concentration necessary to kill S. aureus, lowering the toxic side effects to the host associated with prolonged aminoglycoside exposure. IMPORTANCE Staphylococcus aureus infects every niche of the human host, and these infections are the leading cause of Gram-positive sepsis. Aminoglycoside antibiotics are inexpensive, stable, and effective against many bacterial infections. However, S. aureus can shift its metabolism to become tolerant of aminoglycosides, requiring increased concentrations and/or longer courses of treatment, which can cause severe host toxicity. Here, we report that polyunsaturated fatty acids (PUFAs), which have low host toxicity, disrupt the S. aureus membrane, making the pathogen susceptible to aminoglycosides. Additionally, cotreatment with aminoglycosides is effective at killing S. aureus small colony variants, strains that are difficult to treat with antibiotics. Taken together, the data presented herein show the promise of PUFA cotreatment to increase the efficacy of aminoglycosides against S. aureus infections and decrease the risk to the human host of antibiotic-induced toxicity.

Dataset Information

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

Publications

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

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