title: Campylobacter jejuni induces colitis through activation of mammalian target of rapamycin signaling.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Xiaolun
authors.initials: X
authors.lastname: Sun
authors.forename: Deborah
authors.initials: D
authors.lastname: Threadgill
authors.forename: Christian
authors.initials: C
authors.lastname: Jobin
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology; D002169:Campylobacter Infections / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000382:microbiology* / Q000473:pathology / Q000517:prevention & control; D016123:Campylobacter jejuni / Q000472:pathogenicity*; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000378:metabolism; D003092:Colitis / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000382:microbiology* / Q000473:pathology / Q000517:prevention & control; D003106:Colon / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D018836:Inflammation Mediators / Q000378:metabolism; D007274:Injections, Intraperitoneal; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D016328:NF-kappa B / Q000235:genetics; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology / Q000382:microbiology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; C098680:Il17a protein, mouse; D018836:Inflammation Mediators; D020381:Interleukin-17; D053583:Interleukin-1beta; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; C485184:enhanced green fluorescent protein; D016753:Interleukin-10; D049452:Green Fluorescent Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus