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

• Published in: PloS one Vol. 8; no. 7; p. e69846
• Main Authors: Jafari, Nazila V, Kuehne, Sarah A, Bryant, Clare E, Elawad, Mamoun, Wren, Brendan W, Minton, Nigel P, Allan, Elaine, Bajaj-Elliott, Mona
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.07.2013; Public Library of Science (PLoS)
• Subjects: Animals; Antibiotics; Bacteria; Biology; Biomedical research; Bone marrow; Cell activation; Cell cycle; Cell Line; Chemokines; Childrens health; Clostridia; Clostridioides difficile - immunology; Clostridium difficile; Clostridium Infections - immunology; Crosstalk; Cytokines; Dendritic cells; Diarrhea; E coli; Epidemics; Escherichia coli; Gastroenterology; Genomes; Helper cells; Hospitals; Immunity; Immunity, Innate - immunology; Infections; Infectious diseases; Inflammasomes; Innate immunity; Interferon; Interleukin 12; Interleukin 22; Interleukin 23; Interleukin 6; Interleukin 8; Interleukin-12 - metabolism; Interleukin-1beta - metabolism; Interleukin-23 - metabolism; Interleukin-6 - metabolism; Life sciences; Lymphocytes T; Medicine; Mice; Monocytes; Mortality; Mucosa; Pathogenesis; Proteins; Strains (organisms); Toxins; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0069846

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.