The natural human adaptive IgG-specific immune response is skewed towards non-protective tail domains of DNABII proteins

TL;DR

The immune system tends to target non-protective parts of DNABII proteins, which may hinder biofilm clearance, suggesting a vaccine could redirect this response.

Contribution

A new vaccine candidate is proposed to redirect the immune response toward protective domains of DNABII proteins.

Findings

74 out of 77 sera showed IgG-specific preferential recognition of non-protective DNABII domains.

A monoclonal antibody targeting protective DNABII domains disrupts biofilms and improves disease resolution.

A synthetic peptide mimicking protective domains induces an effective immune response.

Abstract

Biofilm-mediated infections are highly recalcitrant to antibiotics and host immune system clearance. The matrix that envelopes biofilm-resident bacteria is stabilized by extracellular DNA as well as integrated ubiquitous bacterial DNABII proteins that exhibit potential as a common therapeutic target. We’ve shown that a monoclonal antibody directed against the immunoprotective DNA-binding ‘tips’ of DNABII proteins disrupts diverse biofilms, prevents their formation, and augments disease resolution in four distinct pre-clinical models. As an immunogen, a synthetic peptide that mimics the immunoprotective domains induces a response with equivalent effectiveness. Confoundingly, however, sera from both children with chronic otitis media (OM) and healthy adults preferentially recognize non-protective ‘tail’ domains of DNABII proteins. Thus, we wondered if this is a universal, natural immune response that contributes to biofilm recalcitrance. Here, we used both surface plasmon resonance and ELISA assays to assess sera from 16 healthy children, 16 additional children with chronic OM, 15 adults with chronic obstructive pulmonary disease, and 30 people with cystic fibrosis for relative recognition of synthetic peptides that mimicked either the protective or the non-protective DNABII protein domains. In 74 of 77 sera assessed (96%), we found significant IgG-specific preferential immune recognition of non-protective domains. These new data support continued development of our DNABII-directed vaccine candidate designed to re-direct the immune response toward the protective domains to mediate biofilm eradication.

Figures