title: High-sensitivity monoclonal antibodies specific for homoserine lactones protect mice from lethal Pseudomonas aeruginosa infections.
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.
authors.affiliation: Scottish Biologics Facility, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
authors.forename: Soumya
authors.initials: S
authors.lastname: Palliyil
authors.forename: Christina
authors.initials: C
authors.lastname: Downham
authors.forename: Ian
authors.initials: I
authors.lastname: Broadbent
authors.forename: Keith
authors.initials: K
authors.lastname: Charlton
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Porter
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000382:microbiology; D003429:Cross Reactions; D007106:Immune Sera; D051379:Mice; D008815:Mice, Inbred Strains; D010196:Pancreatic Elastase / Q000276:immunology / Q000378:metabolism; D019151:Peptide Library; D011552:Pseudomonas Infections / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity*; D053038:Quorum Sensing; D012756:Sheep
chemical_list: D000911:Antibodies, Monoclonal; D007106:Immune Sera; D019151:Peptide Library; C088386:homoserine lactone; D010196:Pancreatic Elastase; D015107:4-Butyrolactone