Clostridium difficile modulates host innate immunity via toxin-independent and dependent mechanism(s)

Jafari, Nazilla V. and Kuehne, Sarah A. and Bryant, Clare E. and Elawad, Mamoun and Wren, Brendan W. and Minton, Nigel P. and Allan, Elaine and Bajaj-Elliott, Mona (2013) Clostridium difficile modulates host innate immunity via toxin-independent and dependent mechanism(s). PLoS ONE, 8 (7). e69846/1-e69846/10. ISSN 1932-6203

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Abstract

Clostridium difficile infection (CDI) is the leading cause of hospital and community-acquired antibiotic-associated diarrhoea and currently represents a significant health burden. Although the role and contribution of C. difficile toxins to disease pathogenesis is being increasingly understood, at present other facets of C. difficile-host interactions, in particular, bacterial-driven effects on host immunity remain less studied. Using an ex-vivo model of infection, we report that the human gastrointestinal mucosa elicits a rapid and significant cytokine response to C. difficile. Marked increase in IFN-γ with modest increase in IL-22 and IL-17A was noted. Significant increase in IL-8 suggested potential for neutrophil influx while presence of IL-12, IL-23, IL-1β and IL-6 was indicative of a cytokine milieu that may modulate subsequent T cell immunity. Majority of C. difficile-driven effects on murine bone-marrow-derived dendritic cell (BMDC) activation were toxin-independent; the toxins were however responsible for BMDC inflammasome activation. In contrast, human monocyte-derived DCs (mDCs) released IL-1β even in the absence of toxins suggesting host-specific mediation. Infected DC-T cell crosstalk revealed the ability of R20291 and 630 WT strains to elicit a differential DC IL-12 family cytokine milieu which culminated in significantly greater Th1 immunity in response to R20291. Interestingly, both strains induced a similar Th17 response. Elicitation of mucosal IFN-γ/IL-17A and Th1/Th17 immunity to C. difficile indicates a central role for this dual cytokine axis in establishing antimicrobial immunity to CDI.

Item Type: Article
Schools/Departments: University of Nottingham UK Campus > Faculty of Medicine and Health Sciences > School of Life Sciences
Depositing User: Minton, Professor Nigel P
Date Deposited: 19 Nov 2013 14:20
Last Modified: 13 Sep 2016 22:34
URI: http://eprints.nottingham.ac.uk/id/eprint/2224

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