Campylobacter jejuni induces colitis through activation of mammalian target of rapamycin signaling

Gastroenterology. 2012 Jan;142(1):86-95.e5. doi: 10.1053/j.gastro.2011.09.042. Epub 2011 Oct 1.

Abstract

Background & aims: Campylobacter jejuni is the worldwide leading cause of bacterial-induced enteritis. The molecular and cellular events that lead to campylobacteriosis are poorly understood. We identify mammalian target of rapamycin (mTOR) as a signaling pathway that leads to C jejuni-induced intestinal inflammation.

Methods: Germ-free (control) or conventionally derived Il10(-/-) mice that express enhanced green fluorescent protein (EGFP) under the control of nuclear factor κB (Il10(-/-); NF-κB(EGFP) mice) were infected with C jejuni (10(9) colony-forming units/mouse) for 12 days; their responses were determined using histologic, semiquantitative reverse-transcription polymerase chain reaction, fluorescence in situ hybridization, transmission electron microscopy, and tissue culture analyses. mTOR signaling was blocked by daily intraperitoneal injections of the pharmacologic inhibitor rapamycin (1.5 mg/kg). CD4(+) T cells were depleted by intraperitoneal injections of antibodies against CD4 (0.5 mg/mouse every 3 days). Bacterial survival in splenocytes was measured using a gentamycin killing assay.

Results: C jejuni induced intestinal inflammation, which correlated with activation of mTOR signaling and neutrophil infiltration. The inflamed intestines of these mice had increased levels of interleukin-1β, Cxcl2, interleukin-17a, and EGFP; C jejuni localized to colons and extraintestinal tissues of infected Il10(-/-); NF-κB(EGFP) mice compared with controls. Rapamycin, administered before or after introduction of C jejuni, blocked C jejuni-induced intestinal inflammation and bacterial accumulation. LC3II processing and killing of C jejuni were increased in splenocytes incubated with rapamycin compared with controls.

Conclusions: mTOR signaling mediates C jejuni-induced colitis in Il10(-/-) mice, independently of T-cell activation. Factors involved in mTOR signaling might be therapeutic targets for campylobacteriosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Video-Audio Media

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / microbiology
  • Campylobacter Infections / complications
  • Campylobacter Infections / genetics
  • Campylobacter Infections / immunology
  • Campylobacter Infections / microbiology*
  • Campylobacter Infections / pathology
  • Campylobacter Infections / prevention & control
  • Campylobacter jejuni / pathogenicity*
  • Cells, Cultured
  • Chemokine CXCL2 / metabolism
  • Colitis / enzymology
  • Colitis / genetics
  • Colitis / immunology
  • Colitis / microbiology*
  • Colitis / pathology
  • Colitis / prevention & control
  • Colon / drug effects
  • Colon / enzymology
  • Colon / immunology
  • Colon / microbiology*
  • Colon / pathology
  • Disease Models, Animal
  • Enzyme Activation
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • In Situ Hybridization, Fluorescence
  • Inflammation Mediators / metabolism
  • Injections, Intraperitoneal
  • Interleukin-10 / deficiency
  • Interleukin-10 / genetics
  • Interleukin-17 / metabolism
  • Interleukin-1beta / metabolism
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • NF-kappa B / genetics
  • Neutrophil Infiltration
  • Neutrophils / immunology
  • Neutrophils / microbiology
  • Protein Kinase Inhibitors / administration & dosage
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction* / drug effects
  • Sirolimus / administration & dosage
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism*
  • Time Factors

Substances

  • Chemokine CXCL2
  • Cxcl2 protein, mouse
  • Il17a protein, mouse
  • Inflammation Mediators
  • Interleukin-17
  • Interleukin-1beta
  • NF-kappa B
  • Protein Kinase Inhibitors
  • enhanced green fluorescent protein
  • Interleukin-10
  • Green Fluorescent Proteins
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases
  • Sirolimus