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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

Clare E. Bryant

Mamoun Elawad

Brendan W. Wren

NIGEL MINTON nigel.minton@nottingham.ac.uk
Professor of Appliedmolecular Microbiology

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.

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

Journal Article Type Article
Publication Date Jul 29, 2013
Deposit Date Nov 19, 2013
Publicly Available Date Mar 24, 2014
Journal PLoS ONE
Electronic ISSN 1932-6203
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 8
Issue 7
Article Number e69846
DOI https://doi.org/10.1371/journal.pone.0069846
Public URL http://eprints.nottingham.ac.uk/id/eprint/2224
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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