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.

Antibodies toStaphylococcus aureuscapsular polysaccharides 5 and 8 perform similarlyin vitrobut are functionally distinctin vivo

“…Passive immunization with CP5 or CP8 antibodies has shown protection in rodent models of mastitis, bacteremia, endocarditis, and skin abscesses. 25,[39][40][41] Despite their failure in clinical trials when used alone in hemodialysis patients, 42,43 CP5 and CP8 conjugate vaccines are thought to be important components in a multivalent staphylococcal vaccine. 1,25,38,44 Because diverse S. aureus clinical isolates (both methicillin-sensitive and -resistant) produce surface-associated CP5 or CP8, 14,15,37 we considered that mAbs to CP5 or CP8 with opsonic activity might be included in a mAb cocktail to prevent or reduce staphylococcal bacteremia.…”

Why antibodies disobey the Hippocratic Oath and end up doing harm: a new clue

“…These mechanisms involve either one antibody type (a, c, and d) or two antibody types that have different functions (b). In contrast, the failure of antibodymediated protection described by Skurnik and colleagues involves two antibody types (to CP and dPNAG) that interfere with one another despite having the same function (enhancing neutrophil-mediated opsonic killing of S. aureus) (9).…”

“…Although a vaccine for strains that do not express CP8 or CP5 (PentaStaph) is in clinical trials, disappointing results with existing investigational CP-based vaccines and immunotherapy highlight the fact that the mechanisms behind their lack of efficacy against S. aureus-associated disease are vexing and mysterious. However, in this issue of the JCI, Skurnik and colleagues provide a fascinating explanation for this phenomenon (9).…”

“…Hence, it is logical to hypothesize that in combination, CP-and dPNAGspecif ic antibodies would enhance opsonic activity and that combining CP and dPNAG in a vaccine could enhance its efficacy against S. aureus. However, Skurnik and colleagues report the startling and unexpected finding that when combined, CP- and dPNAG-specific antibodies inhibit, rather than enhance, neutrophil-mediated killing of S. aureus, promote intracellular bacterial persistence in vitro, and drastically reduce antibody efficacy in vivo in different mouse models of S. aureus disease (9). Antibodies that fail to mediate a biological effect in vitro or host benefit in vivo following natural infection or immunization are well described in human disease and animal models.…”

“…Skurnik and colleagues found that although charge interactions contributed to the binding between CP- and dPNAG-specific antibodies, this binding was highly specific for the antibody types used and was not recapitulated by substituting an antibody to another charged antigen (9). IgG2 dimer formation provides yet another mechanism whereby human serum antibodies can bind to one another (20,21).…”