Enterotoxin-producing Staphylococci Cause Intestinal Inflammation by a Combination of Direct Epithelial Cytopathy and Superantigen-Mediated T-cell Activation

Inflamm Bowel Dis. 2012 Apr;18(4):624-40. doi: 10.1002/ibd.21852. Epub 2011 Sep 1.

Abstract

Background: Enterotoxin-producing Staphylococcus aureus may cause severe inflammatory intestinal disease, particularly in infants or immunodeficient or elderly patients. They are also recognized to be associated with sudden infant death syndrome. Little is known, however, about mucosal responses to staphylococci.

Methods: The mucosal lesion in three infants with staphylococcal enterocolitis was assessed by immunohistochemistry and electron microscopy. The organisms underwent extensive molecular analysis. Their toxins were assessed for capacity to induce T-cell activation and host mucosal responses examined by in vitro organ culture. Epithelial responses were studied by coculture with HEp-2 and Caco-2 cells.

Results: Intestinal biopsies from the patients showed marked epithelial damage with mucosal inflammation. The three staphylococci, representing two distinct clones, were methicillin-sensitive, producing SEG/I enterotoxins and Rho-inactivating EDIN toxins. Their enterotoxins potently activated T cells, but only whole organisms could induce in vitro enteropathy, characterized by remarkable epithelial desquamation uninhibited by tacrolimus. EDIN-producing staphylococci, but not their supernatants, induced striking cytopathy in HEp-2 epithelial cells but not in Caco-2 cells. Although HEp-2 and Caco-2 cells produced similar IL-8, CCL20, and cathelicidin LL37 responses upon bacterial exposure, only Caco-2 cells expressed mRNA for the β-defensins HBD2 and HBD3, while HEp-2 cells were unable to do so.

Conclusions: Staphylococci induce enterocolitis by a combination of direct enterocyte cytopathy mediated by EDIN toxins, disrupting the epithelial barrier, and enterotoxin superantigen-induced mucosal T-cell activation. Gut epithelial production of β-defensins may contribute to host defense against invasive staphylococcal disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biopsy
  • Cell Line
  • Coculture Techniques
  • Enterocolitis / immunology*
  • Enterocolitis / microbiology
  • Enterocolitis / pathology
  • Enterotoxins / immunology
  • Enterotoxins / toxicity
  • Female
  • Humans
  • Infant
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / pathology
  • Lymphocyte Activation / immunology*
  • Male
  • Staphylococcal Infections / immunology*
  • Staphylococcal Infections / pathology
  • Staphylococcus aureus / immunology
  • Staphylococcus aureus / ultrastructure
  • Superantigens / immunology*
  • T-Lymphocytes / immunology*
  • Tacrolimus
  • beta-Defensins / biosynthesis

Substances

  • Enterotoxins
  • Superantigens
  • beta-Defensins
  • Tacrolimus