Bacterial virulence factor inhibits caspase-4/11 activation in intestinal epithelial cells.
The human pathogen enteropathogenic Escherichia coli (EPEC), as well as the mouse pathogen Citrobacter rodentium, colonize the gut mucosa via attaching and effacing lesion formation and cause diarrheal diseases. EPEC and C. rodentium type III secretion system (T3SS) effectors repress innate immune responses and infiltration of immune cells. Inflammatory caspases such as caspase-1 and caspase-4/11 are crucial mediators of host defense and inflammation in the gut via their ability to process cytokines such as interleukin (IL)-1β and IL-18. Here we report that the effector NleF binds the catalytic domain of caspase-4 and inhibits its proteolytic activity. Following infection of intestinal epithelial cells (IECs) EPEC inhibited caspase-4 and IL-18 processing in an NleF-dependent manner. Depletion of caspase-4 in IECs prevented the secretion of mature IL-18 in response to infection with EPECΔnleF. NleF-dependent inhibition of caspase-11 in colons of mice prevented IL-18 secretion and neutrophil influx at early stages of C. rodentium infection. Neither wild-type C. rodentium nor C. rodentiumΔnleF triggered neutrophil infiltration or IL-18 secretion in Cas11 or Casp1/11-deficient mice. Thus, IECs have a key role in modulating early innate immune responses in the gut via a caspase-4/11-IL-18 axis, which is targeted by virulence factors encoded by enteric pathogens.
Department of Life Sciences, MRC Centre for Molecular Bacteriology and Infection, Imperial College, London, UK.
M A
MA
Pallett
Department of Life Sciences, MRC Centre for Molecular Bacteriology and Infection, Imperial College, London, UK.
V F
VF
Crepin
Innate Immunity Unit, Institut Pasteur, Paris, France.|Inserm U668, Paris, France.
N
N
Serafini
Department of Life Sciences, MRC Centre for Molecular Bacteriology and Infection, Imperial College, London, UK.
M
M
Habibzay
Department of Life Sciences, MRC Centre for Molecular Bacteriology and Infection, Imperial College, London, UK.
O
O
Kotik
Department of Medicine, MRC Centre for Molecular Bacteriology and Infection, Imperial College, London, UK.
J
J
Sanchez-Garrido
Innate Immunity Unit, Institut Pasteur, Paris, France.|Inserm U668, Paris, France.
J P
JP
Di Santo
Department of Medicine, MRC Centre for Molecular Bacteriology and Infection, Imperial College, London, UK.
A R
AR
Shenoy
Department of Life Sciences, MRC Centre for Molecular Bacteriology and Infection, Imperial College, London, UK.
C N
CN
Berger
Department of Life Sciences, MRC Centre for Molecular Bacteriology and Infection, Imperial College, London, UK.
G
G
Frankel
D000818:Animals; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D053471:Caspases, Initiator / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D044082:Citrobacter rodentium / Q000276:immunology* / Q000472:pathogenicity; D004756:Enterobacteriaceae Infections / Q000276:immunology*; D054308:Enteropathogenic Escherichia coli / Q000276:immunology* / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000276:immunology*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D020382:Interleukin-18 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
D029968:Escherichia coli Proteins; D020382:Interleukin-18; C583422:NleF protein, E coli; D034741:RNA, Small Interfering; D037521:Virulence Factors; C093516:CASP4 protein, human; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator