High-sensitivity monoclonal antibodies specific for homoserine lactones protect mice from lethal Pseudomonas aeruginosa infections

Soumya Palliyil, Christina Downham, Ian Broadbent, Keith Charlton, Andrew J Porter

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

A number of bacteria, including pathogens like Pseudomonas aeruginosa, utilize homoserine lactones (HSLs) as quorum sensing (QS) signaling compounds and engage in cell-to-cell communication to coordinate their behavior. Blocking this bacterial communication may be an attractive strategy for infection control as QS takes a central role in P. aeruginosa biology. In this study, immunomodulation of HSL molecules by monoclonal antibodies (MAbs) was used as a novel approach to prevent P. aeruginosa infections and as tools to detect HSLs in bodily fluids as a possible first clue to an undiagnosed Gram-negative infection. Using sheep immunization and recombinant antibody technology, a panel of sheep-mouse chimeric MAbs were generated which recognized HSL compounds with high sensitivity (nanomolar range) and cross-reactivity. These MAbs retained their nanomolar sensitivity in complex matrices and were able to recognize HSLs in P. aeruginosa cultures grown in the presence of urine. In a nematode slow-killing assay, HSL MAbs significantly increased the survival of worms fed on the antibiotic-resistant strain PA058. The therapeutic benefit of these MAbs was further studied using a mouse model of Pseudomonas infection in which groups of mice treated with HSL-2 and HSL-4 MAbs survived, 7 days after pathogen challenge, in significantly greater numbers (83 and 67%, respectively) compared with the control groups. This body of work has provided early proof-of-concept data to demonstrate the potential of HSL-specific, monoclonal antibodies as theranostic clinical leads suitable for the diagnosis, prevention, and treatment of life-threatening bacterial infections.

Original languageEnglish
Pages (from-to)462-469
Number of pages8
JournalApplied and Environmental Microbiology
Volume80
Issue number2
Early online date1 Nov 2013
DOIs
Publication statusPublished - Jan 2014

Keywords

  • 4-Butyrolactone
  • Animals
  • Antibodies, Monoclonal
  • Caenorhabditis elegans
  • Cross Reactions
  • Immune Sera
  • Mice
  • Mice, Inbred Strains
  • Pancreatic Elastase
  • Peptide Library
  • Pseudomonas Infections
  • Pseudomonas aeruginosa
  • Quorum Sensing
  • Sheep

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