title: A peptide antagonist of CD28 signaling attenuates toxic shock and necrotizing soft-tissue infection induced by Streptococcus pyogenes.
abstract: Staphylococcus aureus and group A Streptococcus pyogenes (GAS) express superantigen (SAg) exotoxin proteins capable of inducing lethal shock. To induce toxicity, SAgs must bind not only to the major histocompatibility complex II molecule of antigen-presenting cells and the variable β chain of the T-cell receptor but also to the dimer interface of the T-cell costimulatory receptor CD28. Here, we show that the CD28-mimetic peptide AB103 (originally designated "p2TA") protects mice from lethal challenge with streptococcal exotoxin A, as well as from lethal GAS bacterial infection in a murine model of necrotizing soft-tissue infection. Administration of a single dose of AB103 increased survival when given up to 5 hours after infection, reduced inflammatory cytokine expression and bacterial burden at the site of infection, and improved muscle inflammation in a dose-dependent manner, without compromising cellular and humoral immunity. Thus, AB103 merits further investigation as a potential therapeutic in SAg-mediated necrotizing soft-tissue infection.
authors.affiliation: Center for Vaccine Development, University of Maryland Medical School, Baltimore, Baltimore, MD 21201, USA.
authors.forename: Girish
authors.initials: G
authors.lastname: Ramachandran
authors.forename: Mohan E
authors.initials: ME
authors.lastname: Tulapurkar
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Harris
authors.forename: Gila
authors.initials: G
authors.lastname: Arad
authors.forename: Anat
authors.initials: A
authors.lastname: Shirvan
authors.forename: Ronen
authors.initials: R
authors.lastname: Shemesh
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Detolla
authors.forename: Cinzia
authors.initials: C
authors.lastname: Benazzi
authors.forename: Steven M
authors.initials: SM
authors.lastname: Opal
authors.forename: Raymond
authors.initials: R
authors.lastname: Kaempfer
authors.forename: Alan S
authors.initials: AS
authors.lastname: Cross
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D018106:CD28 Antigens / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D015169:Colony Count, Microbial; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005098:Exotoxins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000633:toxicity; D005260:Female; D007111:Immunity, Cellular; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D012772:Shock, Septic / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D015398:Signal Transduction; D018461:Soft Tissue Infections / Q000188:drug therapy / Q000382:microbiology; D013047:Specific Pathogen-Free Organisms; D013290:Streptococcal Infections / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000276:immunology* / Q000378:metabolism; D018089:Superantigens / Q000276:immunology / Q000633:toxicity*; D037521:Virulence Factors
chemical_list: D000907:Antibodies, Bacterial; D018106:CD28 Antigens; D016207:Cytokines; D005098:Exotoxins; D010455:Peptides; D018089:Superantigens; D037521:Virulence Factors
keywords: CD28; group A S. pyogenes; necrotizing soft tissue infection; peptide antagonist; superantigen