A peptide antagonist of CD28 signaling attenuates toxic shock and necrotizing soft-tissue infection induced by Streptococcus pyogenes

J Infect Dis. 2013 Jun 15;207(12):1869-77. doi: 10.1093/infdis/jit104. Epub 2013 Mar 14.

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.

Keywords: CD28; group A S. pyogenes; necrotizing soft tissue infection; peptide antagonist; superantigen.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Bacterial / immunology
  • CD28 Antigens / antagonists & inhibitors
  • CD28 Antigens / immunology*
  • CD28 Antigens / metabolism
  • Cell Proliferation
  • Colony Count, Microbial
  • Cytokines / blood
  • Cytokines / immunology
  • Dose-Response Relationship, Drug
  • Exotoxins / antagonists & inhibitors
  • Exotoxins / immunology
  • Exotoxins / toxicity
  • Female
  • Immunity, Cellular
  • Mice
  • Mice, Inbred BALB C
  • Peptides / pharmacology
  • Peptides / therapeutic use*
  • Shock, Septic / drug therapy*
  • Shock, Septic / immunology
  • Shock, Septic / microbiology
  • Signal Transduction
  • Soft Tissue Infections / drug therapy
  • Soft Tissue Infections / microbiology
  • Specific Pathogen-Free Organisms
  • Streptococcal Infections / drug therapy*
  • Streptococcal Infections / immunology
  • Streptococcal Infections / microbiology
  • Streptococcus pyogenes / immunology*
  • Streptococcus pyogenes / metabolism
  • Superantigens / immunology
  • Superantigens / toxicity*
  • Virulence Factors

Substances

  • Antibodies, Bacterial
  • CD28 Antigens
  • Cytokines
  • Exotoxins
  • Peptides
  • Superantigens
  • Virulence Factors