title: VLP-based vaccine induces immune control of Staphylococcus aureus virulence regulation.
abstract: Staphylococcus aureus is the leading cause of skin and soft tissue infections (SSTIs) and mounting antibiotic resistance requires innovative treatment strategies. S. aureus uses secreted cyclic autoinducing peptides (AIPs) and the accessory gene regulator (agr) operon to coordinate expression of virulence factors required for invasive infection. Of the four agr alleles (agr types I-IV and corresponding AIPs1-4), agr type I isolates are most frequently associated with invasive infection. Cyclization via a thiolactone bond is essential for AIP function; therefore, recognition of the cyclic form of AIP1 may be necessary for antibody-mediated neutralization. However, the small sizes of AIPs and labile thiolactone bond have hindered vaccine development. To overcome this, we used a virus-like particle (VLP) vaccine platform (PP7) for conformationally-restricted presentation of a modified AIP1 amino acid sequence (AIP1S). Vaccination with PP7-AIP1S elicited AIP1-specific antibodies and limited agr-activation in vivo. Importantly, in a murine SSTI challenge model with a highly virulent agr type I S. aureus isolate, PP7-AIP1S vaccination reduced pathogenesis and increased bacterial clearance compared to controls, demonstrating vaccine efficacy. Given the contribution of MRSA agr type I isolates to human disease, vaccine targeting of AIP1-regulated virulence could have a major clinical impact in the fight against antibiotic resistance.
authors.affiliation: University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA.
authors.forename: Seth M
authors.identifier: http://orcid.org/0000-0002-3532-8810
authors.initials: SM
authors.lastname: Daly
authors.affiliation: University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Joyner
authors.affiliation: University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA.
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Triplett
authors.affiliation: University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA.
authors.forename: Bradley O
authors.initials: BO
authors.lastname: Elmore
authors.affiliation: University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA.
authors.forename: Srijana
authors.initials: S
authors.lastname: Pokhrel
authors.affiliation: University of New Mexico School of Medicine, Department of Molecular Genetics and Microbiology, Albuquerque, NM, 87131, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Frietze
authors.affiliation: University of New Mexico School of Medicine, Department of Molecular Genetics and Microbiology, Albuquerque, NM, 87131, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Peabody
authors.affiliation: University of New Mexico School of Medicine, Department of Molecular Genetics and Microbiology, Albuquerque, NM, 87131, USA.
authors.forename: Bryce
authors.initials: B
authors.lastname: Chackerian
authors.affiliation: University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM, 87131, USA. phall@salud.unm.edu.
authors.forename: Pamela R
authors.identifier: http://orcid.org/0000-0003-2367-3382
authors.initials: PR
authors.lastname: Hall
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial; D001426:Bacterial Proteins / Q000737:chemistry / Q000276:immunology; D004195:Disease Models, Animal; D007114:Immunization; D051379:Mice; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D010456:Peptides, Cyclic / Q000737:chemistry / Q000276:immunology; D011487:Protein Conformation; D013203:Staphylococcal Infections / Q000276:immunology* / Q000517:prevention & control*; D013209:Staphylococcal Vaccines / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology* / Q000472:pathogenicity*; D058425:Vaccines, Virus-Like Particle / Q000276:immunology*; D014774:Virulence / Q000276:immunology*
chemical_list: C414532:AgrD protein, Staphylococcus; D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D010455:Peptides; D010456:Peptides, Cyclic; D013209:Staphylococcal Vaccines; D058425:Vaccines, Virus-Like Particle