title: A peptide immunization approach to counteract a Staphylococcus aureus protease defense against host immunity.
abstract: Pathogens that induce acute and chronic infections, as well as certain cancers, employ numerous strategies to thwart host cellular and humoral immune defenses. One proposed evasion mechanism against humoral immunity is a localized expression of extracellular proteases that cleave the IgG hinge and disable host IgG functions. Host immunity appears to be prepared to counter such a proteolytic tactic by providing a group of autoantibodies, denoted anti-hinge antibodies that specifically bind to cleaved IgGs and provide compensating functional restoration in vitro. These respective counter-measures highlight the complex interrelationships among pathogens and host immunity and suggested to us a possible means for therapeutic intervention. In this study, we combined an investigation of pathogen-mediated proteolysis of host IgGs with an immunization strategy to boost host anti-hinge antibodies. In a Staphylococcus aureus infection model using an artificial tissue cage (wiffle ball) implanted into rabbits, cleaved rabbit IgGs were detected in abundance in the abscesses of untreated animals early after infection. However, in animals previously immunized with peptide analogs of the cleaved IgG hinge to generate substantial anti-hinge antibody titers, S. aureus colony formation was markedly reduced compared to control animals or those similarly immunized with a scrambled peptide sequence. The results of this study demonstrate that extensive local proteolysis of IgGs occurs in a test abscess setting and that immunization to increase host anti-hinge antibodies provided substantial acute protection against bacterial growth.
authors.affiliation: Biologics Research, Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477 USA. Electronic address: bjonmemel@gmail.com.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Jordan
authors.affiliation: Infectious Diseases and Vaccines, Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, USA. Electronic address: jfernan5@its.jnj.com.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Fernandez
authors.affiliation: Biologics Research, Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477 USA.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Brezski
authors.affiliation: Biologics Research, Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477 USA.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Greenplate
authors.affiliation: Biologics Research, Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477 USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Knight
authors.affiliation: Biologics Research, Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477 USA.
authors.forename: T Shantha
authors.initials: TS
authors.lastname: Raju
authors.affiliation: Infectious Diseases and Vaccines, Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, USA.
authors.forename: A Simon
authors.initials: AS
authors.lastname: Lynch
mesh_terms: D000038:Abscess / Q000276:immunology*; D000818:Animals; D058491:Bacterial Load; D004195:Disease Models, Animal; D004338:Drug Combinations; D005620:Freund's Adjuvant / Q000276:immunology; D006433:Hemocyanins / Q000235:genetics; D006801:Humans; D057131:Immune Evasion; D056724:Immunity, Humoral; D007114:Immunization; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010936:Plant Extracts; D059748:Proteolysis; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D013203:Staphylococcal Infections / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology*
chemical_list: D004338:Drug Combinations; D007074:Immunoglobulin G; D010446:Peptide Fragments; D010936:Plant Extracts; D011993:Recombinant Fusion Proteins; C119572:bearberry, bladderwrack, borage oil, centella, fatty acid, fish oil, ginkgo biloba, melilotus, soya lecithin drug combination; D005620:Freund's Adjuvant; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin
keywords: Anti-hinge antibodies; In vivo; Rabbit; Staphylococcus aureus; Tissue cage; Vaccination