Attaching and effacing bacterial effector NleC suppresses epithelial inflammatory responses by inhibiting NF-κB and p38 mitogen-activated protein kinase activation

Infect Immun. 2011 Sep;79(9):3552-62. doi: 10.1128/IAI.05033-11. Epub 2011 Jul 11.

Abstract

Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli are noninvasive attaching and effacing (A/E) bacterial pathogens that cause intestinal inflammation and severe diarrheal disease. These pathogens utilize a type III secretion system to deliver effector proteins into host epithelial cells, modulating diverse cellular functions, including the release of the chemokine interleukin-8 (IL-8). While studies have implicated the effectors NleE (non-locus of enterocyte effacement [LEE]-encoded effector E) and NleH1 in suppressing IL-8 release, by preventing NF-κB nuclear translocation, the impact of these effectors only partially replicates the immunosuppressive actions of wild-type EPEC, suggesting another effector or effectors are involved. Testing an array of EPEC mutants, we identified the non-LEE-encoded effector C (NleC) as also suppressing IL-8 release. Infection by ΔnleC EPEC led to exaggerated IL-8 release from infected Caco-2 and HT-29 epithelial cells. NleC localized to EPEC-induced pedestals, with signaling studies revealing NleC inhibits both NF-κB and p38 mitogen-activated protein kinase (MAPK) activation. Using Citrobacter rodentium, a mouse-adapted A/E bacterium, we found that ΔnleC and wild-type C. rodentium-infected mice carried similar pathogen burdens, yet ΔnleC strain infection led to worsened colitis. Similarly, infection with ΔnleC C. rodentium in a cecal loop model induced significantly greater chemokine responses than infection with wild-type bacteria. These studies thus advance our understanding of how A/E pathogens subvert host inflammatory responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Adhesion
  • Caco-2 Cells
  • Chemokines / metabolism
  • Citrobacter rodentium / genetics
  • Citrobacter rodentium / pathogenicity*
  • Colitis / microbiology
  • Enterobacteriaceae Infections / immunology
  • Enterobacteriaceae Infections / microbiology*
  • Enteropathogenic Escherichia coli / genetics
  • Enteropathogenic Escherichia coli / pathogenicity*
  • Epithelial Cells / immunology
  • Escherichia coli Proteins / genetics
  • Escherichia coli Proteins / metabolism*
  • Fluorescent Antibody Technique
  • HT29 Cells
  • Humans
  • Interleukin-8 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Polymerase Chain Reaction
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Chemokines
  • Escherichia coli Proteins
  • Interleukin-8
  • NF-kappa B
  • Z0986 protein, E coli
  • p38 Mitogen-Activated Protein Kinases