Abstract
We have previously described a native human monoclonal antibody, TRL1068, that disrupts bacterial biofilms by extracting from the biofilm matrix key scaffolding proteins in the DNABII family, which are present in both gram positive and gram negative bacterial species. The antibiotic resistant sessile bacteria released from the biofilm then revert to the antibiotic sensitive planktonic state. Qualitative resensitization to antibiotics has been demonstrated in three rodent models of acute infections. We report here the surprising discovery that antibodies against the target family were found in all twenty healthy humans surveyed, albeit at a low level requiring a sensitive single B-cell assay for detection. We have cloned 21 such antibodies. Aside from TRL1068, only one (TRL1330) has all the biochemical properties believed necessary for pharmacological efficacy (broad spectrum epitope specificity and high affinity). We suggest that the other anti-DNABII antibodies, while not necessarily curative, reflect an immune response at some point in the donor’s history to these components of biofilms. Such an immune response could reflect exposure to bacterial reservoirs that have been previously described in chronic non-healing wounds, periodontal disease, chronic obstructive pulmonary disease, colorectal cancer, rheumatoid arthritis, and atherosclerotic artery explants. The detection of anti-DNABII antibodies in all twenty surveyed donors with no active infection suggests that bacterial biofilm reservoirs may be present periodically in most healthy individuals. Biofilms routinely shed bacteria, creating a continuous low level inflammatory stimulus. Since chronic subclinical inflammation is thought to contribute to most aging-related diseases, suppression of bacterial biofilm has potential value in delaying age-related pathology.
Highlights
Many serious bacterial infections are difficult to treat due to formation of a biofilm matrix, which protects the bacterial cells from attack by the cellular immune system and induces a physiological shift from the planktonic to a slower growing sessile state [1]
Three recombinant DNABII proteins with diverse sequences were used for the primary screen: HU from S. aureus, Integration Host Factor (IHF) from K. pneumoniae, and IHF from H. influenzae with a fourth bead type coated with BSA as a control for non-specific binding
Since the mammalian proteome does not have any homologs to DNABII proteins, the presence of memory B-cells producing anti-DNABII antibodies in an individual donor’s repertoire suggests that the individual has been exposed to the bacterial antigen, consistent with its presence extracellularly as part of a biofilm [25]
Summary
Many serious bacterial infections are difficult to treat due to formation of a biofilm matrix, which protects the bacterial cells from attack by the cellular immune system and induces a physiological shift from the planktonic (free floating) to a slower growing sessile (adherent) state [1]. Antibiotic sensitivity differs between these two states, with biofilm associated bacteria typically showing as much as 1000-fold less sensitivity to antibiotics. Human antibodies against a key bacterial biofilm component was provided from an SBIR grant from US National Institute of Allergy and Infectious Diseases to LK: 5SB1AI120425-04, https://sbir.nih.gov/niaid/index
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