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

Jafari, Nazilla V.; Kuehne, Sarah A.; Bryant, Clare E.; Elawad, Mamoun; Wren, Brendan W.; Minton, Nigel P.; Allan, Elaine; Bajaj-Elliott, Mona

Authors

Nazilla V. Jafari

Sarah A. Kuehne sarah.keuhne@nottingham.av.uk

Clare E. Bryant

Mamoun Elawad

Brendan W. Wren brendan.wren@lshtm.ac.uk

Nigel P. Minton nigel.minton@nottingham.ac.uk

Elaine Allan

Mona Bajaj-Elliott

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.

Journal Article Type Article
Publication Date Jul 29, 2013
Journal PLoS ONE
Electronic ISSN 1932-6203
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 8
Issue 7
Article Number e69846
Institution Citation Jafari, N. V., Kuehne, S. A., Bryant, C. E., Elawad, M., Wren, B. W., Minton, N. P., …Bajaj-Elliott, M. (2013). Clostridium difficile modulates host innate immunity via toxin-independent and dependent mechanism(s). PLoS ONE, 8(7), doi:10.1371/journal.pone.0069846
DOI https://doi.org/10.1371/journal.pone.0069846
Publisher URL http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0069846
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0




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