Antibody Dependent Enhancement ofAcinetobacter baumanniiInfection in a Mouse Pneumonia Model

Abstract

Acinetobacter baumannii has become a pathogen of increasing medical importance because of the emergence of multidrugresistant strains and the high rate of mortality of infected patients. Promising animal study results have been reported recently with active and passive immunization against A. baumannii virulence factors. In the present study, a monoclonal IgG3 antibody, 8E3, was developed with specificity for the K2 capsular polysaccharide of A. baumannii, and its therapeutic potential was assessed. 8E3 enhanced macrophage-mediated bactericidal activity against the A. baumannii clinical strain AB899. However, 8E3 treatment (passive immunization) of AB899-infected mice led to a substantial increase in mortality and to substantial increases in bacterial load in blood, lung, and in splenic samples. In vitro investigations showed a large binding capacity in the supernatant of bacterial cultures, suggesting that shed capsule components act as a binding sink for 8E3. Investigations of 8E3 pharmacokinetics in mice demonstrated that unbound concentrations of the antibody dropped below detection limits within 24 hours after a 200 mg/kg dose. However, total concentrations of antibody declined slowly, with an apparent terminal half-life (t 1/2 ) of 6.7-8.0 days, suggesting that the vast majority of 8E3 in blood is bound (e.g., with soluble capsule components in blood). We hypothesize that high concentrations of 8E3-capsule immune complexes act to inhibit bacterial clearance in vivo. To the best of our knowledge, this is the first demonstration of antibodydependent enhancement of A. baumannii infection, and these observations highlight the complexity of antibody-based therapy for A. baumannii infections.

Specific egg yolk immunoglobulin as a promising non-antibiotic biotherapeutic product against Acinetobacter baumannii pneumonia infection

“…Despite higher absorbance in ELISA, specific IgY triggered against the combination of OmpA and Omp34 unexpectedly exacerbated disease in comparison to other IgYs 19 . In addition to the study, which was the first report on antibody-dependent enhancement (ADE) of A. baumannii infection, recently, this phenomenon has also been reported on a mAb developed against K2 capsular polysaccharide of A. baumannii 28 . The study suggests that the capsule could act as decoys interacting with the mAb 28 .…”

Antibody-Dependent Enhancement of Bacterial Disease: Prevalence, Mechanisms, and Treatment

“…Acinetobacter baumannii pneumonia, the passive immunization of a monoclonal antibody (mAb) specific for the capsule increased mortality and bacterial burden in the blood, lung and spleen (18). The presence of these antibodies were found to increase adhesion of the bacteria to resiraptory epithelial cells (18).…”

“…Acinetobacter baumannii pneumonia, the passive immunization of a monoclonal antibody (mAb) specific for the capsule increased mortality and bacterial burden in the blood, lung and spleen (18). The presence of these antibodies were found to increase adhesion of the bacteria to resiraptory epithelial cells (18). In a mouse model of Neisseria gonnorrhoaea infection, passive immunization with mAb towards the reduction modifiable protein (Rmp) abrogated the protective effects of the 2c7 mAb (19), causing both increased bacterial burden and duration of infection (20).…”

“…The function of this dynamic process of capsule-shedding or restructuring has been described for evasion of host immune defences, potentially providing insight to explain antibody-mediated enhancement of bacterial infection. Wang-lin et al (18) reported that a mechanism of ADE exists for A. baumannii…”

Host-Malaria Parasite Interactions and Impacts on Mutual Evolution

“…A partial protective vaccine may also prime the immune system in some individuals that can mount a strong inflammatory response when infected, leading to enhanced severe symptoms. Another related possibility is ADE that was observed in various viral infections, including Dengue virus (Waggoner et al, 2020), influenza (Winarski et al, 2019), Zika virus (Asad et al, 2019), coronavirus (Negro, 2020;Wan et al, 2020), and Acinetobacter baumannii bacteria (Wang-Lin et al, 2019). ADE is a well-known mechanism that viruses or bacteria may infect susceptible cells by interacting with antibodies or complement components (Fc or complement receptors), leading to enhanced viral entry into host cells and/or higher replication rate.…”