title: Critical Role of Alpha-Toxin and Protective Effects of Its Neutralization by a Human Antibody in Acute Bacterial Skin and Skin Structure Infections.
abstract: Methicillin-resistant Staphylococcus aureus (MRSA) causes large-scale epidemics of acute bacterial skin and skin structure infections (ABSSSI) within communities across the United States. Animal models that reproduce ABSSSI as they occur in humans are urgently needed to test new therapeutic strategies. Alpha-toxin plays a critical role in a variety of staphylococcal infection models in mice, but its role in the pathogenesis of ABSSSI remains to be elucidated in rabbits, which are similar to humans in their susceptibility to S. aureus superantigens and certain bicomponent pore-forming leukocidins. We report here a new rabbit model of ABSSSI and show that those infected with a mutant deficient in expression of alpha-toxin (Δhla) developed a small dermonecrotic lesion, whereas those infected with isogenic USA300 MRSA wild-type or complemented Δhla strains developed ABSSSI that mimic the severe infections that occur in humans, including the large central dermonecrotic core surrounded by erythema, induration, and marked subcutaneous hemorrhage. More importantly, immunoprophylaxis with MEDI4893*, an anti-alpha-toxin human monoclonal antibody, significantly reduced the severity of disease caused by a USA300 wild-type strain to that caused by the Δhla mutant, indicating that this toxin could be completely neutralized during infection. Thus, this study illustrates a potential high standard for the development of new immunotherapeutic agents in which a toxin-neutralizing antibody provides protection to the same degree achieved with a toxin gene knockout. When MEDI4893* was administered as adjunctive therapy with a subtherapeutic dose of linezolid, the combination was significantly more efficacious than either agent alone in reducing the severity of ABSSSI.
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Vien T M
authors.initials: VT
authors.lastname: Le
authors.affiliation: Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, Maryland, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Tkaczyk
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Sally
authors.initials: S
authors.lastname: Chau
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Renee L
authors.initials: RL
authors.lastname: Rao
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Etyene Castro
authors.initials: EC
authors.lastname: Dip
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Eliane P
authors.initials: EP
authors.lastname: Pereira-Franchi
authors.affiliation: Department of Pathology, MedImmune, LLC, Gaithersburg, Maryland, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Pathology, MedImmune, LLC, Gaithersburg, Maryland, USA.
authors.forename: Sally
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Pathology, MedImmune, LLC, Gaithersburg, Maryland, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Koelkebeck
authors.affiliation: Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, Maryland, USA.
authors.forename: Jamese J
authors.initials: JJ
authors.lastname: Hilliard
authors.affiliation: Translational Sciences, MedImmune, LLC, Gaithersburg, Maryland, USA.
authors.forename: Xiang Qing
authors.initials: XQ
authors.lastname: Yu
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Vivekananda
authors.initials: V
authors.lastname: Datta
authors.affiliation: Pre-Clinical Services, University of North Texas Health Sciences Center, Fort Worth, Texas, USA.
authors.forename: Vien
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: Pre-Clinical Services, University of North Texas Health Sciences Center, Fort Worth, Texas, USA.
authors.forename: William
authors.initials: W
authors.lastname: Weiss
authors.affiliation: Pre-Clinical Services, University of North Texas Health Sciences Center, Fort Worth, Texas, USA.
authors.forename: Laszlo
authors.identifier: 0000-0002-4559-3458
authors.initials: L
authors.lastname: Prokai
authors.affiliation: Statistical Sciences, MedImmune, LLC, Gaithersburg, Maryland, USA.
authors.forename: Terrence
authors.initials: T
authors.lastname: O'Day
authors.affiliation: Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, Maryland, USA.
authors.forename: C Kendall
authors.initials: CK
authors.lastname: Stover
authors.affiliation: Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, Maryland, USA SellmanB@MedImmune.com binh.diep@ucsf.edu.
authors.forename: Bret R
authors.initials: BR
authors.lastname: Sellman
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA SellmanB@MedImmune.com binh.diep@ucsf.edu.
authors.forename: Binh An
authors.initials: BA
authors.lastname: Diep
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology*; D000080908:Broadly Neutralizing Antibodies; D004195:Disease Models, Animal; D006460:Hemolysin Proteins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D000069349:Linezolid / Q000097:blood / Q000494:pharmacology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D065129:Pre-Exposure Prophylaxis / Q000379:methods; D011817:Rabbits; D017192:Skin Diseases, Bacterial / Q000276:immunology / Q000382:microbiology*; D013207:Staphylococcal Skin Infections / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D001427:Bacterial Toxins; D000080908:Broadly Neutralizing Antibodies; D006460:Hemolysin Proteins; C021091:staphylococcal alpha-toxin; C000600718:suvratoxumab; D000069349:Linezolid