Human α-defensin 6 promotes mucosal innate immunity through self-assembled peptide nanonets

Science. 2012 Jul 27;337(6093):477-81. doi: 10.1126/science.1218831. Epub 2012 Jun 21.

Abstract

Defensins are antimicrobial peptides that contribute broadly to innate immunity, including protection of mucosal tissues. Human α-defensin (HD) 6 is highly expressed by secretory Paneth cells of the small intestine. However, in contrast to the other defensins, it lacks appreciable bactericidal activity. Nevertheless, we report here that HD6 affords protection against invasion by enteric bacterial pathogens in vitro and in vivo. After stochastic binding to bacterial surface proteins, HD6 undergoes ordered self-assembly to form fibrils and nanonets that surround and entangle bacteria. This self-assembly mechanism occurs in vivo, requires histidine-27, and is consistent with x-ray crystallography data. These findings support a key role for HD6 in protecting the small intestine against invasion by diverse enteric pathogens and may explain the conservation of HD6 throughout Hominidae evolution.

Publication types

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

MeSH terms

  • Adhesins, Bacterial / metabolism
  • Animals
  • Bacterial Proteins / metabolism
  • Cell Line
  • Humans
  • Immunity, Innate*
  • Immunity, Mucosal*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / microbiology
  • Intestinal Mucosa / ultrastructure
  • Intestine, Small / immunology*
  • Intestine, Small / microbiology
  • Intestine, Small / ultrastructure
  • Macromolecular Substances / chemistry
  • Macromolecular Substances / immunology
  • Macromolecular Substances / metabolism
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron, Scanning
  • Models, Molecular
  • Nanostructures
  • Paneth Cells / immunology
  • Paneth Cells / metabolism
  • Peptides / chemistry
  • Peptides / metabolism
  • Protein Binding
  • Protein Multimerization
  • Protein Structure, Quaternary
  • Salmonella Infections, Animal / immunology
  • Salmonella Infections, Animal / microbiology
  • Salmonella typhimurium / immunology
  • Salmonella typhimurium / pathogenicity
  • Salmonella typhimurium / ultrastructure
  • Yersinia enterocolitica / immunology
  • Yersinia enterocolitica / pathogenicity
  • alpha-Defensins / chemistry*
  • alpha-Defensins / immunology
  • alpha-Defensins / metabolism*
  • env Gene Products, Human Immunodeficiency Virus / metabolism

Substances

  • Adhesins, Bacterial
  • Bacterial Proteins
  • Macromolecular Substances
  • Peptides
  • alpha-Defensins
  • alpha-defensin 6, human
  • env Gene Products, Human Immunodeficiency Virus
  • invasin, Yersinia