Clostridium difficile modulates host innate immunity via toxin-independent and dependent mechanism(s).
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.
Infectious Diseases and Microbiology Unit, Institute of Child Health, University College London, London, United Kingdom.
Nazila V
NV
Jafari
Sarah A
SA
Kuehne
Clare E
CE
Bryant
Mamoun
M
Elawad
Brendan W
BW
Wren
Nigel P
NP
Minton
Elaine
E
Allan
Mona
M
Bajaj-Elliott
D000818:Animals; D002460:Cell Line; D016360:Clostridioides difficile / Q000276:immunology*; D003015:Clostridium Infections / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D018664:Interleukin-12 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice
D053583:Interleukin-1beta; D053759:Interleukin-23; D015850:Interleukin-6; D018664:Interleukin-12