Bacterial virulence factor inhibits caspase-4/11 activation in intestinal epithelial cells

Pallett, M. A., Crepin, V. F., Serafini, N., Habibzay, M., Kotik, O., Sanchez-Garrido, J., Di Santo, J. P., Shenoy, A. R., Berger, C. N. ORCID: https://orcid.org/0000-0002-1316-5985 and Frankel, G. 2017. Bacterial virulence factor inhibits caspase-4/11 activation in intestinal epithelial cells. Mucosal Immunology 10 , pp. 602-612. 10.1038/mi.2016.77

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	Nature Publishing Group
ISSN:	1933-0219
Date of First Compliant Deposit:	6 September 2018
Date of Acceptance:	1 August 2016
Last Modified:	06 Nov 2023 18:58
URI:	https://orca.cardiff.ac.uk/id/eprint/114738

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