title: Passive therapy with humanized anti-staphylococcal enterotoxin B antibodies attenuates systemic inflammatory response and protects from lethal pneumonia caused by staphylococcal enterotoxin B-producing Staphylococcus aureus.
abstract: Drugs such as linezolid that inhibit bacterial protein synthesis may be beneficial in treating infections caused by toxigenic Staphylococcus aureus. As protein synthesis inhibitors have no effect on preformed toxins, neutralization of pathogenic exotoxins with anti-toxin antibodies may be beneficial in conjunction with antibacterial therapy. Herein, we evaluated the efficacy of human-mouse chimeric high-affinity neutralizing anti-staphylococcal enterotoxin B (SEB) antibodies in the treatment of experimental pneumonia caused by SEB-producing S. aureus. Since HLA class II transgenic mice mount a stronger systemic immune response following challenge with SEB and are more susceptible to SEB-induced lethal toxic shock than conventional mice strains, HLA-DR3 transgenic mice were used. Lethal pneumonia caused by SEB-producing S. aureus in HLA-DR3 transgenic mice was characterized by robust T cell activation and elevated systemic levels of several pro-inflammatory cytokines and chemokines. Prophylactic administration of a single dose of linezolid 30 min prior to the onset of infection attenuated the systemic inflammatory response and protected from mortality whereas linezolid administered 60 min after the onset of infection failed to confer significant protection. Human-mouse chimeric high-affinity neutralizing anti-SEB antibodies alone, but not polyclonal human IgG, mitigated this response and protected from death when administered immediately after initiation of infection. Further, anti-SEB antibodies as well as intact polyclonal human IgG, but not its Fab or Fc fragments, protected from lethal pneumonia when followed with linezolid therapy 60 min later. In conclusion, neutralization of superantigens with high-affinity antibodies may have beneficial effects in pneumonia.
authors.affiliation: a Division of Clinical Microbiology , Department of Laboratory Medicine and Pathology , Mayo Clinic College of Medicine , Rochester , MN , USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Karau
authors.affiliation: b Department of Veterinary and Animal Sciences , University of Massachusetts , Amherst , MA , USA.|c Department of Biology , Amherst College , Amherst , MA , USA.
authors.forename: Mulualem E
authors.initials: ME
authors.lastname: Tilahun
authors.affiliation: d Department of Immunology , Mayo Clinic College of Medicine , Rochester , MN , USA.
authors.forename: Ashton
authors.initials: A
authors.lastname: Krogman
authors.affiliation: b Department of Veterinary and Animal Sciences , University of Massachusetts , Amherst , MA , USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Osborne
authors.affiliation: c Department of Biology , Amherst College , Amherst , MA , USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Goldsby
authors.affiliation: d Department of Immunology , Mayo Clinic College of Medicine , Rochester , MN , USA.
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
authors.affiliation: e Division of Biomedical Statistics and Informatics , Department of Health Sciences Research , Mayo Clinic College of Medicine , Rochester , MN , USA.
authors.forename: Jayawant N
authors.initials: JN
authors.lastname: Mandrekar
authors.affiliation: a Division of Clinical Microbiology , Department of Laboratory Medicine and Pathology , Mayo Clinic College of Medicine , Rochester , MN , USA.|f Division of Infectious Diseases , Department of Medicine , Mayo Clinic College of Medicine , Rochester , MN , USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Patel
authors.affiliation: d Department of Immunology , Mayo Clinic College of Medicine , Rochester , MN , USA.|f Division of Infectious Diseases , Department of Medicine , Mayo Clinic College of Medicine , Rochester , MN , USA.
authors.forename: Govindarajan
authors.initials: G
authors.lastname: Rajagopalan
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004768:Enterotoxins / Q000235:genetics / Q000276:immunology*; D015803:HLA-DR3 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D007116:Immunization, Passive; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011014:Pneumonia / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000628:therapy*; D013203:Staphylococcal Infections / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000628:therapy*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D004768:Enterotoxins; D015803:HLA-DR3 Antigen; C031818:enterotoxin B, staphylococcal
keywords: HLA class II transgenic mice; T lymphocytes; pneumonia; staphylococcus aureus; superantigen