The K1 Capsular Polysaccharide from Acinetobacter baumannii Is a Potential Therapeutic Target via Passive Immunization

Abstract

fThe emergence of extremely resistant and panresistant Gram-negative bacilli, such as Acinetobacter baumannii, requires consideration of nonantimicrobial therapeutic approaches. The goal of this report was to evaluate the K1 capsular polysaccharide from A. baumannii as a passive immunization target. Its structure was determined by a combination of mass spectrometric and nuclear magnetic resonance (NMR) techniques. Molecular mimics that might raise the concern for autoimmune disease were not identified. Immunization of CD1 mice demonstrated that the K1 capsule is immunogenic. The monoclonal antibody (MAb) 13D6, which is directed against the K1 capsule from A. baumannii, was used to determine the seroprevalence of the K1 capsule in a collection of 100 A. baumannii strains. Thirteen percent of the A. baumannii isolates from this collection were seroreactive to MAb 13D6. Opsonization of K1-positive strains, but not K1-negative strains, with MAb 13D6 significantly increased neutrophil-mediated bactericidal activity in vitro (P < 0.05). Lastly, treatment with MAb 13D6 3 and 24 h after bacterial challenge in a rat soft tissue infection model resulted in a significant decrease in the growth/survival of a K1-positive strain compared to that of a K1-negative strain or to treatment with a vehicle control (P < 0.0001). These data support the proof of principle that the K1 capsule is a potential therapeutic target via passive immunization. Other serotypes require assessment, and pragmatic challenges exist, such as the need to serotype infecting strains and utilize serotype-specific therapy. Nonetheless, this approach may become an important therapeutic option with increasing antimicrobial resistance and a diminishing number of active antimicrobials.

Clinical and Pathophysiological Overview of Acinetobacter Infections: a Century of Challenges

“…In one compelling study, the investigators used the lack of virulence of the lab-adapted A. baumannii strain ATCC 17978 to demonstrate a remarkable gain of function of virulence by treating the strain with small molecules that triggered overexpression of capsule (107). Recent elucidation of the O-glycation systems in A. baumannii has begun to clarify capsular chemical structures that protect against innate defenses; A. baumannii glycation favors short-chain, branched, negatively charged amino-containing surface sugars which both protect against host immunity and may serve as a target for future immune interventions to help clear the pathogen (111)(112)(113)(114)(115)(116).…”

“…Nearly 40 serotypes have been identified in A. baumannii, and the prevalence of each serotype is largely unknown. A monoclonal antibody targeting the K1 capsular polysaccharide recognized only 13% of Acinetobacter strains (113). Capsule is an attractive target for an antibody-based vaccine, but such a vaccine would have to be multivalent given the number of different capsular types that might need to be included.…”

Pathogenic Acinetobacter: from the Cell Surface to Infinity and Beyond

“…Carbohydrate structures present in Acinetobacter, such as the capsule and glycoproteins, represent attractive antigenic targets for vaccine development; since the carbohydrate moieties are the same in both, targeting these structures may provide broad protection (46). Indeed, capsule-based vaccines have shown efficacy in soft tissue, pneumonia, and bacteremia rodent models (116,117). A drawback to this approach, however, is that the strain-to-strain variations in carbohydrate structures are so great that a multivalent vaccine to target all pathogenic Acinetobacter strains is unrealistic.…”

Physiology and Pathology of Multidrug-Resistant Bacteria: Antibodies- and Vaccines-Based Pathogen-Specific Targeting

“…Immunization of mice with sub-lethal and K1 capsular polysaccharide positive A. baumannii induced generation of speciic anti-K1 capsular polysaccharide IgM monoclonal antibody (13D6) [183]. Moreover, 13D6 can induce eicient neutrophil-mediated in vitro opsonization and in vivo passive protectivity in rat soft tissue infection model [183]. However, only 13% of 100 collected A. baumannii strains were positive against 13D6, suggesting other capsular polysaccharide serotypes that may be unexplored.…”