Clostridium difficile Modulates Host Innate Immunity via Toxin-Independent and Dependent Mechanism(s)

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.

A MLST Clade 2 Clostridium difficile strain with a variant TcdB induces severe inflammatory and oxidative response associated with mucosal disruption

“…IL-1 is one of the main cytokines involved in the immune response to C. difficile toxins [48] and its secretion has been related to the activation of the inflammasome via iNOS production [49]. Both ICC-45 and NAP1/027 strains induced a high secretion levels of this cytokine.…”

Host Immunity to Clostridium difficile PCR Ribotype 017 Strains

“…C. difficile TcdA and TcdB are known inflammasome activators, a cellular pathway that culminates in IL-1␤ secretion and pyroptosis (26,29). Since CF5 and M68 TcdBs share 100% predicted sequence identity (25), a difference in toxin secretion offered an alternative explanation for the observed differential effect on BMDC IL-1␤ release.…”

“…Primers for cytokine mRNA detection were from Eurofins MEG Operon, Ebersberg, Germany (26), and SYBR green JumpStart Taq ReadyMix was from Sigma-Aldrich. Gene expression of IL-23 p19 subunit was analyzed by using TaqMan probe-based PCR from Applied Biosystems.…”

The roles of host and pathogen factors and the innate immune response in the pathogenesis of Clostridium difficile infection

“…In the human context, C. difficile infection (CDI) is considered the leading cause of hospital and community-acquired antibiotic-associated diarrhea in the western world [1, 2]. This is reflected in the rates of morbidity and mortality with 36,000 cases registered with the UK health protection agency in 2010 alone [3]. The annual incidence of CDI in the USA is more than 3,000,000 cases [4], costing US hospitals an estimated 1-3 billion USD annually [5].…”

“…In fact, the incidence of CDI in some community hospitals is now greater than methicillin-resistant Staphylococcus aureus infections. Alarmingly, CDI is increasingly seen in patients with no recent exposure to antibiotics and in young healthy adults [3]. Some have speculated that the increased rates of hospital and community-acquired CDI, and its increased severity, are associated with enhanced C. difficile virulence.…”