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

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-? 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-1? 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-1? 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-?/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), Article e69846. https://doi.org/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: https://nottingham-repository.worktribe.com/output/716076
• Publisher URL: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0069846