Protein A-Specific Monoclonal Antibodies and Prevention of Staphylococcus aureus Disease in Mice

Kim, Hwan Keun; Emolo, Carla; DeDent, Andrea C.; Falugi, Fabiana; Missiakas, Dominique; Schneewind, Olaf

doi:10.1128/iai.00230-12

Cited by 92 publications

(125 citation statements)

References 49 publications

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“…A number of recent reviews and primary research articles serve to highlight the unique mechanisms by which these factors promote immune evasion (11,19,25,(28)(29)(30). Not only do they work in concert to effectively inhibit clearance of S. aureus by the host immune surveillance, they also prevent the development of immunological memory against this pathogen (31)(32)(33)(34). This combined attack on both innate and adaptive immune defenses is believed to be a major reason why current therapeutic and vaccine strategies, which rely on robust innate and adaptive pathogen recognition, have failed (35)(36)(37)(38).…”

mentioning

confidence: 99%

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

Alonzo

Torres

2014

Microbiol Mol Biol Rev

236

290

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SUMMARY The ability to produce water-soluble proteins with the capacity to oligomerize and form pores within cellular lipid bilayers is a trait conserved among nearly all forms of life, including humans, single-celled eukaryotes, and numerous bacterial species. In bacteria, some of the most notable pore-forming molecules are protein toxins that interact with mammalian cell membranes to promote lysis, deliver effectors, and modulate cellular homeostasis. Of the bacterial species capable of producing pore-forming toxic molecules, the Gram-positive pathogen Staphylococcus aureus is one of the most notorious. S. aureus can produce seven different pore-forming protein toxins, all of which are believed to play a unique role in promoting the ability of the organism to cause disease in humans and other mammals. The most diverse of these pore-forming toxins, in terms of both functional activity and global representation within S. aureus clinical isolates, are the bicomponent leucocidins. From the first description of their activity on host immune cells over 100 years ago to the detailed investigations of their biochemical function today, the leucocidins remain at the forefront of S. aureus pathogenesis research initiatives. Study of their mode of action is of immediate interest in the realm of therapeutic agent design as well as for studies of bacterial pathogenesis. This review provides an updated perspective on our understanding of the S. aureus leucocidins and their function, specificity, and potential as therapeutic targets.

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mentioning

confidence: 99%

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

Alonzo

Torres

2014

Microbiol Mol Biol Rev

236

290

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“…Data presented in our study suggest that blocking the Fcγ and Fab binding activities of SpsQ could be an alternative or adjunct to conventional antimicrobial treatments for infections caused by S. pseudintermedius including canine pyoderma [11]. Canine anti-SpsQ-M may reduce SpsQ immune suppression in dogs, stimulate the production of specific antibodies against S. pseudintermedius and establish a protective immunity against recurrent infection.…”

Section: Discussionmentioning

confidence: 95%

“…This is likely rooted in the ability of the bacteria to evade and/or destroy important components of their host defenses [10,11]. Protein A is anchored on the peptidoglycan cell wall and is also secreted during the exponential growth phase [12–15].…”

Section: Introductionmentioning

confidence: 99%

Characterization of recombinant wild-type and nontoxigenic protein A from Staphylococcus pseudintermedius

2018

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Background: Staphylococcus pseudintermedius is an opportunistic pathogen that is the major cause of pyoderma affecting dogs. Conventional antimicrobial treatment for infections caused by this organism have failed in recent years due to widespread resistance and alternative treatment strategies are a high priority. Protein A encoded in Staphylococcus aureus by spa protects the bacterium by binding IgG and acts as a superantigen. Staphylococcus pseudintermedius possess two genes orthologous to S. aureus spa, spsP, and spsQ. Methods: SpsQ and SpsQ-M, a non-toxigenic SpsQ, were cloned and expressed as recombinant proteins and their cytotoxic effect on canine B cells was measured. The neutralizing ability of antibody raised against them in clinically healthy dogs was evaluated. Results: S. pseudintermedius SpsQ induced apoptosis of canine B cells. Specific amino acid substitutions diminished SpsQ-M binding to immunoglobulin and its super-antigenic activity, while its antigenicity was maintained. This recombinant, non-toxigenic S. pseudintermedius SpsQ stimulated the production of antibodies in dogs that specifically reacted with SpsQ and greatly diminished its cytotoxic effect on canine B cells. Conclusions: The production of neutralizing antibody suggests that attenuated, non-toxic SpsQ produced in this study is a good candidate for inclusion in a vaccine for use in the treatment and prevention of S. pseudintermedius infections.Abbreviations: SpA: Staphylococcus aureus protein A; SpsP: Staphylococcus pseudintermedius protein A; SpsQ: Staphylococcus pseudintermedius protein A; SpsQ-M: attenuated Staphylococcus pseudintermedius protein A; MRSP: methicillin resistant Staphylococcus pseudintermedius; IgA: immunoglobulin A; IgG: immunoglobulin G; IgM: immunoglobulin M; VH: variable region of immunoglobulin heavy chain; IgBD: immunoglobulin binding domains; MFI: mean fluorescent intensity; SEM: standard error of the mean; PBMC: Peripheral blood mononuclear cells; CD21: complement receptor type 2; ST: Sequence type; OD: Optical density; ORF: open reading frame; PBS: Phosphate buffered saline; Tween 20: Polyethylene glycol sorbitan monolaurate 20; HRP: horseradish peroxidase; TMB- 3,3',5,5'-Tetramethylbenzidine

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“…23,49,50 Considering the complexity of the S. aureus disease spectrum, it is likely that a cocktail of mAbs targeting distinct staphylococcal virulence factors may serve to protect against diverse Figure 7. Quantitation of cell-associated and soluble CP5 or CP8 produced by clinical isolates of S. aureus cultivated in RMPI C 1% casamino acids.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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The capsular polysaccharide (CP) produced by Staphylococcus aureus is a virulence factor that allows the organism to evade uptake and killing by host neutrophils. Polyclonal antibodies to the serotype 5 (CP5) and type 8 (CP8) capsular polysaccharides are opsonic and protect mice against experimental bacteremia provoked by encapsulated staphylococci. Thus, passive immunotherapy using CP antibodies has been considered for the prevention or treatment of invasive antibioticresistant S. aureus infections. In this report, we generated monoclonal antibodies (mAbs) against S. aureus CP5 or CP8. Backbone specific mAbs reacted with native and O-deacetylated CPs, whereas Oacetyl specific mAbs reacted only with native CPs. Reference strains of S. aureus and a selection of clinical isolates reacted by colony immunoblot with the CP5 and CP8 mAbs in a serotype-specific manner. The mAbs mediated in vitro CP type-specific opsonophagocytic killing of S. aureus strains, and mice passively immunized with CP5 mAbs were protected against S. aureus bacteremia. Neither CP8-specific mAbs or polyclonal antibodies protected mice against bacteremia provoked by serotype 8 S. aureus clinical isolates, although these same antibodies did protect against a serotype 5 S. aureus strain genetically engineered to produce CP8. We detected soluble CP8 in culture supernatants of serotype 8 clinical isolates and in the plasma of infected animals. Serotype 5 S. aureus released significantly less soluble CP5 in vitro and in vivo. The release of soluble CP8 by S. aureus may contribute to the inability of CP8 vaccines or antibodies to protect against serotype 8 staphylococcal infections.

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Protein A-Specific Monoclonal Antibodies and Prevention of Staphylococcus aureus Disease in Mice

Abstract: ABSTRACTStaphylococcus aureusis a leading cause of human soft tissue infections and bacterial sepsis. The emergence of antibiotic-resistant strains (methicillin-resistantS. aureus[MRSA]) has prompted research into st… Show more

Cited by 92 publications

References 49 publications

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

Characterization of recombinant wild-type and nontoxigenic protein A from Staphylococcus pseudintermedius

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

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