Abstract

Clostridioides difficile is often resistant to the actions of antibiotics to treat other bacterial infections and the resulting C. difficile infection (CDI) is among the leading causes of nosocomial infectious diarrhea worldwide. The primary virulence mechanism contributing to CDI is the production of toxins. Treatment failures and recurrence of CDI have urged the medical community to search for novel treatment options. Strains that do not produce toxins, so called non-toxigenic C. difficile, have been known to colonize the colon and protect the host against CDI. In this review, a comprehensive description and comparison of the immune responses to toxigenic C. difficile and non-toxigenic adherence, and colonization factors, here called non-toxin proteins, is provided. This revealed a number of similarities between the host immune responses to toxigenic C. difficile and non-toxin proteins, such as the influx of granulocytes and the type of T-cell response. Differences may reflect genuine variation between the responses to toxigenic or non-toxigenic C. difficile or gaps in the current knowledge with respect to the immune response toward non-toxigenic C. difficile. Toxin-based and non-toxin-based immunization studies have been evaluated to further explore the role of B cells and reveal that plasma cells are important in protection against CDI. Since the success of toxin-based interventions in humans to date is limited, it is vital that future research will focus on the immune responses to non-toxin proteins and in particular non-toxigenic strains.

Highlights

  • Toxigenic Clostridioides difficile (C. difficile) is a multiply antibiotic resistant, anaerobic bacterium that is among the leading causes of nosocomial infectious diarrhea worldwide

  • Wilson and Sheagren (1983) were the first to show that hamsters pre-treated with cefoxitin and colonized by an non-toxigenic C. difficile (NTCD) were protected against a challenge with a toxigenic C. difficile (TCD) strain

  • Using RT027 C. difficile strain and CdtA- and CdtB- mutants, this study showed that C. difficile transferase (CDT) was able to induce IL-1β production in the inflammasome which suggest that CDT acts as a priming signal for inflammasome formation

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Summary

INTRODUCTION

Toxigenic Clostridioides difficile (C. difficile) is a multiply antibiotic resistant, anaerobic bacterium that is among the leading causes of nosocomial infectious diarrhea worldwide. Wilson and Sheagren (1983) were the first to show that hamsters pre-treated with cefoxitin and colonized by an NTCD were protected against a challenge with a toxigenic C. difficile (TCD) strain They found that hamster survival increased from 21 to 93% (Wilson and Sheagren, 1983). A number of phase I and II trials has been performed to determine safety, efficacy, and colonization rate using the NTCD-M3 strain (Villano et al, 2012; Gerding et al, 2015, 2018) These trials demonstrated that administration of NTCDM3 spores was safe, i.e., no serious adverse events (SAEs) occurred, and effective in preventing subsequent CDI in patients experiencing their first CDI or first recurrent CDI episode (Villano et al, 2012; Gerding et al, 2015). We hope that the overview presented in this review will provide a framework that will aid in the analysis of immunological data from controlled animal or human infection studies in the future

Clostridioides difficile Toxin Production
Tfh cells γδ T cells B cells
Adaptive Immune Responses to Clostridioides difficile and Its Toxins
CONCLUDING REMARKS
Findings
AUTHOR CONTRIBUTIONS
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