The Capsular Polysaccharide of Acinetobacter baumannii Is an Obstacle for Therapeutic Passive Immunization Strategies

has become an important concern for human health due to rapid development and wide spread of antimicrobial-resistant strains and high mortality associated with the infection. Passive immunizations with antisera targeting outer membrane proteins (OMPs) have shown encouraging results in protecting mic...

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Bibliographic Details
Published in:Infection and immunity 2017-12, Vol.85 (12)
Main Authors: Wang-Lin, Shun Xin, Olson, Ruth, Beanan, Janet M, MacDonald, Ulrike, Balthasar, Joseph P, Russo, Thomas A
Format: Article
Language:English
Subjects:
Acinetobacter baumannii - immunology
Acinetobacter baumannii - metabolism
Acinetobacter Infections - therapy
Animals
Antibodies, Bacterial - immunology
Antibodies, Bacterial - therapeutic use
Antibodies, Monoclonal - immunology
Antibodies, Monoclonal - therapeutic use
Bacterial Infections
Bacterial Outer Membrane Proteins - immunology
Blood Bactericidal Activity
Complement System Proteins - metabolism
Disease Models, Animal
Humans
Immunization, Passive
Mice
Polysaccharides, Bacterial - metabolism
Protein Binding
Sepsis - therapy
Treatment Outcome
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Summary:has become an important concern for human health due to rapid development and wide spread of antimicrobial-resistant strains and high mortality associated with the infection. Passive immunizations with antisera targeting outer membrane proteins (OMPs) have shown encouraging results in protecting mice from infection, but monoclonal anti-OMP antibodies have not been developed, and their potential therapeutic properties have not been explored. The goal of this report is to evaluate the antibacterial activity of monoclonal antibodies (MAbs) targeting outer membrane protein A (OmpA) of Five anti-OmpA MAbs were developed using hybridoma technology and showed strong binding to strain ATCC 19606. However, low antibody binding was observed when they were tested against six clinical isolates, which included extensively drug-resistant strains. In contrast, high binding to an isogenic K1 capsule-negative mutant (AB307.30) was shown, suggesting that capsular polysaccharide mediated the inhibition of MAb binding to OmpA. Anti-OmpA MAbs increased the macrophage-mediated bactericidal activity of AB307.30 but failed to increase phagocytic killing of capsule-positive strains. Capsular polysaccharide was also protective against complement-mediated bactericidal activity in human ascites in the presence and absence of opsonization. Lastly, passive immunization with anti-OmpA MAbs did not confer protection against challenge with AB307-0294, the encapsulated parent strain of AB307.30, in a mouse sepsis infection model. These results reveal the important role of capsule polysaccharide in shielding OmpA and thereby inhibiting anti-OmpA MAb binding to clinical isolates. This property of capsule hindered the therapeutic utility of anti-OmpA MAbs, and it may apply to other conserved epitopes in .
ISSN:0019-9567
1098-5522
DOI:10.1128/IAI.00591-17